Quinuclidine derivative having tricyclic hetero condensed ring

ABSTRACT

A quinuclidine derivative represented by the following general formula (I), a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, which has strong squalene synthase inhibiting activity and is useful as a cholesterol lowering agent without causing side effects. ##STR1## (Symbols in the formula represent the following meanings; R 1  : a hydrogen atom, a halogen atom or a lower alkyl group, 
     R 2  : a hydrogen atom, a hydroxyl group or a lower alkoxy group, 
       . . : a single bond or a double bond, with the proviso that 
     R 2  does not exist when . . . is a double bond, 
     X and Y: the same or different from each other and each represents a bond, an oxygen atom (--O--), a carbonyl group (--CO--), a group represented by the formula --S(O) p  -- or a group represented by the formula --NR 3  --, 
     p: 0, 1 or 2, 
     R 3  : a hydrogen atom or a lower alkyl group which may have a substituent, 
     A: a saturated or unsaturated lower alkylene group, a group of the formula --(CH 2 ) m  Z(CH 2 ) n  -- or a group of the formula --(CH 2 ) m  Z(CH 2 ) n  CR 4  =, 
     Z: an oxygen atom (--O--), a group of the formula --S(O) q  --, a carbonyl group (--CO--) or a group of the formula --NR 5  --, 
     R 4  : a hydrogen atom, a halogen atom or a lower alkyl group, 
     R 5  : a hydrogen atom or a lower alkyl group, 
     m and n: the same or different from each other and each is 0 or an integer of 1 to 5, 
     m+n: an integer of 1 to 5 
     q: 0, 1 or 2, 
     with the proviso that, when either one of X and Y is a bond, 
     A is a group represented by the formula --(CH 2 ) m  Z(CH 2 ) n  CR 4  =.)

This application is a 371 of PCT/JP96/00491 filed Mar. 1, 1996.

TECHNICAL FIELD

This invention relates to a novel quinuclidine derivative having atricyclic hetero condensed ring, a salt thereof, a hydrate thereof or asolvate thereof, which has a squalene synthase inhibiting action, and toa squalene synthase inhibitor which contains the compound as the activeingredient.

BACKGROUND ART

It is known that arteriosclerosis induces various diseases. For example,ischemic heart diseases induced by coronary arteriosclerosis have thehighest mortality rate next to cancer in Japan, and it is known thatcerebral infarction induced by cerebral arteriosclerosis is accompaniedby serious secondary diseases such as difficulty of moving, dementia andthe like. In addition, since these various diseases induced byarteriosclerosis have been increasing with the increase in agedpopulation and the changes in the dietary life into European andAmerican styles, great concern has been directed toward the developmentof on effective therapeutic agent.

Increase in the blood cholesterol level is considered important as amain causal factor of arteriosclerosis which is a degenerative diseaseof the artery. Increase in the blood cholesterol firstly causes increasein blood lipid level and deposition of lipid on the inner membrane oflarge blood vessel, and the range and degree of these phenomena increasewith the advance in years, finally causing ischemic heart diseases suchas myocardial infarction, angina pectoris and the like, cerebralarteriosclerotic diseases such as cerebral infarction and the like andclinical symptoms such as aneurysm and the like. In consequence, it isconsidered that inhibition of the increase in blood cholesterol and itsreduction to normal level are markedly effective for the treatment orprevention of the aforementioned various diseases caused byarteriosclerosis.

From the above point of view, attempts have been made to develop varioushyperlipemia-treating agents. Cholesterol in the living body is providedas a portion absorbed from food and another portion synthesized in theliving body and excreted mainly as bile acid. In the case of humans, 50%or more of the total cholesterol is originated from de novo synthesis inthe living body. In consequence, inhibition of an enzyme which isconcerned in the biosynthesis of cholesterol seems to be effective intreating hyperlipemia, and lovastatin, simvastatin and pravastatin arenow clinically used as inhibitors for such an enzyme cf. A. W. Albertset al., Proc. Natl. Acad. Sci., vol. 77, p. 3957 (1980); Tsujita et al.,Biochim. Biophs. Acta, vol. 877, p. 50 (1986); and Koga et al., Biochim.Biophs. Acta, vol. 1045, p. 115 (1990)!.

However; the aforementioned known inhibitors aim at3-hydroxymethylglutaryl coenzyme A reductase (hereinafter, to bereferred to as HMG-CoA reductase) as the target enzyme, and this enzymeis located at a relatively early stage of the cholesterol biosynthesissystem. Accordingly, it is possible that inhibition of the enzyme by theadministration of the aforementioned agents may also induce inhibitionof the synthesis of other important metabolic products such as dolichol,ubiquinone, isopentenyl tRNA, p21Ras, low molecular weight G protein andthe like which are concerned in intracellular information transfer andcell growth (cf. Trends Biochem. Soc., vol. 4, p. 230 (1993), Cell, vol.65, p. 1 (1991)).

In fact, it is known that growth of cells does not occur due tointerruption of the cell cycle when an HMG-CoA reductase inhibitor isadded to the cultured cells (Sakakibara et al., Protein, Nucleic Acidand Enzyme, vol. 39, p. 1508 (1994)), and side effects such as hepaticcytotoxicity and myopathy have also been observed.

In addition, it has been reported that triparanol known as the inhibitorof an enzyme located at a downstream stage of the cholesterolbiosynthesis system accumulates desmosterol which causes the cataracts.

In consequence, an inhibitor which targets squalene synthase, an enzymepositioned at a stage after branching into physiologically importantmetabolic products and before formation of lanosterol that becomes acausal substance for arteriosclerosis, will provide a cholesterolbiosynthesis inhibitor which has more higher safety and does not causeinhibition of the synthesis of other metabolites and does not causeaccumulation of toxic substances in the living body.

Also, the activities of HMG-CoA reductase and squalene synthase are bothdown-regulated by sterol Faust, J. R., Goldstein, J. L. and Brown, M.S., Proc. Nat. Acad. Sci. USA, vol. 76, pp. 5018-5022 (1979)!. In thecase-of HMG-CoA reductase, considerable induction of enzyme activityoccurs when supply of sterol is blocked by inhibiting its activity, thusinevitably requiring increase of the dosage, while such an induction issmall in the case of squalene synthase which therefore can bearefficient reduction of blood cholesterol level without increasing itsdosage.

Several compounds have been known as such inhibitors of squalenesynthase. For example, it is known that certain quinuclidine derivativesdisclosed in international patent publications WO 92/15579, WO 93/13096,WO 93/09115 and WO 95/31458 have squalene synthase inhibiting action andcholesterol biosynthesis inhibiting action. All of these compounds arequinuclidine derivatives having two independents rings such as biphenylgroup and the like as substituents.

On the other hand, WO 93/15073 shows compounds by a general formula inwhich an azabicyclo ring such as of quinuclidine or the like is linkedto an aromatic ring or hetero aromatic ring via an alkylene chain whichmay have one hetero atom or unsaturated bond. Of these compounds,however, only compounds having dibenzofuran are illustratively disclosedas compounds which have hetero aromatic rings, particularly tricyclichetero condensed rings, and nothing is illustratively disclosed orsuggested about other compounds having tricyclic hetero condensed rings.That is, only three compounds of ##STR2## are illustratively disclosed.In addition, their use is calcium channel antagonist, and nothing isdisclosed or suggested about the cholesterol biosynthesis inhibitingaction or squalene synthase inhibiting action.

As described in the foregoing, various studies have been made, butdevelopment of an excellent squalene synthase inhibitor is still animportant subject from clinical point of view.

DISCLOSURE OF THE INVENTION

In carrying out a study to find a compound having squalene synthaseinhibiting action, the inventors of the present invention have conducteda synthesis study with a focus of a quinuclidine derivative which has atricyclic hetero condensed ring. We have conducted the synthesis studyalso with a focus on the bonding moiety between the quinuclidine and thetricyclic hetero condensed ring. As the result, it was found that anovel quinuclidine derivative having a specified tricyclic heterocondensed ring, represented by the following general formula (I), has astrong squalene synthase inhibiting action, resulting in theaccomplishment of the present invention. It was also found that acompound represented by the following general formula (I) in which thebonding moiety between the quinuclidine and the tricyclic heterocondensed ring is a specified carbon chain (--(CH₂)_(m) Z(CH₂)_(n) CR₄=) having a double bond on its terminal has a strong squalene synthaseinhibiting action.

Thus, the object of the present invention is to provide cholesterolbiosynthesis inhibitors, particularly a squalene synthase inhibitorrepresented by the following general formula (I) whose chemicalstructure is different from those of the prior art compounds and whichis excellent in terms of markedly reduced side effects and highersafety, for example, showing less danger of inhibiting the synthesis ofother metabolites and accumulating toxic substances in the living body.

In addition, the object of the present invention is to provide amedicine having squalene synthase inhibiting activity, which contains anovel quinuclidine derivative having a tricyclic hetero condensed ring,represented by the following general formula (I), a pharmaceuticallyacceptable salt thereof, a hydrate thereof or a solvate thereof as itsactive ingredient, or a pharmaceutical composition which comprises thecompound (I) of the present invention, a pharmaceutically acceptablesalt thereof, a hydrate thereof or a solvate thereof and apharmaceutically acceptable carrier. ##STR3## (Symbols in the formulahave the following meanings; R₁ : a hydrogen atom, a halogen atom or alower alkyl group,

R₂ : a hydrogen atom, a hydroxyl group or a lower alkoxy group,

. . : a single bond or a double bond,

with the proviso that R₂ does not exist when . . . is a double bond,

X and Y: the same or different from each other and each represents abond, an oxygen atom (--O--), a carbonyl group (--CO--), a grouprepresented by the formula --S(O)_(p) -- or a group represented by theformula --NR₃ --,

p: 0, 1 or 2,

R₃ : a hydrogen atom or a lower alkyl group which may have asubstituent,

A: a saturated or unsaturated lower alkylene group, a group representedby the formula --(CH₂)_(m) Z(CH₂)_(n) -- or a group represented by theformula --(CH₂)_(m) Z(CH₂)_(n) CR₄ =,

Z: an oxygen atom (--O--), a group represented by the formula --S(O)_(q)--, a carbonyl group (--CO--) or a group represented by the formula--NR₅ --,

R₄ : a hydrogen atom, a halogen atom or a lower alkyl group,

R₅ : a hydrogen atom or a lower alkyl group,

m and n: the same or different from each other and each is 0 or aninteger of 1 to 5,

m+n: an integer of 1 to 5, and

q: 0, 1 or 2,

with the proviso that A is a group represented by the formula--(CH₂)_(m) Z(CH₂)_(n) CR₄ = when either one of X and Y is a bond.)

Preferred compounds include a compound (I) of the present invention inwhich A is an unsaturated lower alkylene group, a group represented bythe formula --(CH₂)_(m) Z(CH₂)_(n) -- or a group represented by theformula --(CH₂)_(m) Z(CH₂)_(n) CR₄ = and Z is an oxygen atom (--O--), acarbonyl group (--CO--) or a group represented by the formula --NR₅ --,more preferably a compound (I) of the present invention in which thetricyclic group represented by ##STR4## in the general formula (I) is##STR5## and R₃ is a hydrogen atom or a lower alkyl group which may havea hydroxyl group, a lower alkoxy group, an amino group, a mono- ordi-lower alkylamino group, a carboxyl group, a lower alkoxycarbonylgroup, a carbamoyl group, a mono- or di-lower alkylcarbamoyl group or anaryl group as its substituent, most preferably a compound (I) of thepresent invention in which A is a group represented by the formula--(CH₂)_(m) O(CH₂)_(n) CR₄ =, and most particularly preferred is (Z)-3-2-(carbazol-2-yloxy)ethylidene!quinuclidine, a salt thereof, a hydratethereof or a solvate thereof; (Z)-3-2-(carbazol-2-yloxy)-1-methylethylidene!quinuclidine, a salt thereof, ahydrate thereof or a solvate thereof; or (E)-3-2-(carbazol-2-yloxy)-1-fluoroethylidene!quinuclidine, a salt thereof, ahydrate thereof or a solvate thereof.

The pharmaceutical composition as another object of the presentinvention is a pharmaceutical composition which contains a quinuclidinederivative represented by the general formula (I') or a pharmaceuticallyacceptable salt thereof as its active ingredient, a pharmaceuticalcomposition which uses the compound (I') of the present invention havingsqualene synthase inhibiting activity as its active ingredient, apharmaceutical composition as a cholesterol lowering agent which usesthe compound (I') of the present invention having squalene synthaseinhibiting activity as its active ingredient, particularly apharmaceutical composition which uses the compound (I') of the presentinvention having squalene synthase inhibiting activity as its activeingredient and is a drug for use in the prevention or treatment ofhyperlipemia, arteriosclerosis, aneurysm, ischemic heart diseases suchas myocardial infarction, angina pectoris and the like and cerebralarteriosclerotic diseases such as cerebral infarction and the like.##STR6## (Symbols in the formula represent the following meanings; R₁ :a hydrogen atom, a halogen atom or a lower alkyl group,

R₂ : a hydrogen atom, a hydroxyl group or a lower alkoxy group,

. . : a single bond or a double bond,

with the proviso that R₂ does not exist when . . . is a double bond,

X and Y: the same or different from each other and each represents abond, an oxygen atom (--O--), a carbonyl group (--CO--), a grouprepresented by the formula --S(O)_(p) -- or a group represented by theformula --NR₃ --,

p: 0, 1 or 2,

R₃ : a hydrogen atom or a lower alkyl group which may have asubstituent,

A': a saturated or unsaturated lower alkylene group, a group representedby the formula --(CH₂)_(m) Z(CH₂)_(n) -- or a group represented by theformula --(CH₂)_(m) Z(CH₂)_(n) CR₄ =,

Z: an oxygen atom (--O--), a group represented by the formula --S(O)_(q)--, a carbonyl group (--CO--) or a group represented by the formula--NR₅ --,

R₄ : a hydrogen atom, a halogen atom or a lower alkyl group,

R₅ : a hydrogen atom or a lower alkyl group,

m and n: the same or different from each other and each is 0 or aninteger of 1 to 5,

m+n: an integer of 1 to 5, and

q: 0, 1 or 2.)

The following describes the compound (I) of the present invention indetail.

In the definition of the formulae of this specification, unlessotherwise noted, the term "lower" means a straight or branched carbonchain having 1 to 6 carbon atoms.

Thus, illustrative examples of the "lower alkyl group" include methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl(amyl), isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl,1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl,1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl and the like, of whichalkyl groups having 1 to 4 carbon atoms are preferred, and methyl,ethyl, propyl, isopropyl and butyl groups are particularly preferred.

Illustrative examples of the "lower alkoxy group" include methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,pentyloxy (amyloxy), isopentyloxy, tert-pentyloxy, neopentyloxy,2-methylbutoxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy and thelike, of which methoxy group and ethoxy group are particularlypreferred.

Illustrative examples of the "halogen atom" include fluorine, chlorine,bromine and iodine atoms, of which fluorine and chlorine atoms arepreferred and fluorine atom is particularly preferred.

With respect to the "saturated or unsaturated lower alkylene group" ofA, the saturated lower alkylene group is a straight or branched alkylenegroup having 1 to 6 carbon atoms, and its illustrative examples includemethylene, ethylene, ethylidene, trimethylene, isopropylidene,propylene, tetramethylene, pentamethylene, hexamethylene and the like,of which alkylene groups having 1 to 4 carbon atoms are preferred.

The unsaturated lower alkylene group means an alkenylene or alkynylenegroup having 2 to 6 carbon atoms, and its illustrative examples includevinylene (--CH=CH--), propenylene (--CH=CHCH₂ --), butenylene(--CH=CHCH₂ CH₂ --, --CH₂ CH=CHCH₂ --), pentenylene (--CH=CHCH₂ CH₂ CH₂--, --CH₂ CH=CHCH₂ CH₂ --), hexenylene (--CH=CHCH₂ CH₂ CH₂ CH₂ --, --CH₂CH=CHCH₂ CH₂ CH₂ --, --CH₂ CH₂ CH=CHCH₂ CH₂ --), ethynylene(--C.tbd.C--), propynylene (--C.tbd.CCH₂ --), butynylene (--C.tbd.CCH₂CH₂ --, --CH₂ C.tbd.CCH₂ --), pentynylene (--C.tbd.CCH₂ CH₂ CH₂ --,--CH₂ C.tbd.CCH₂ CH₂ --), hexynylene (--C.tbd.CCH₂ CH₂ CH₂ CH₂ --, --CH₂C.tbd.CCH₂ CH₂ CH₂ --, --CH₂ CH₂ C.tbd.CCH₂ CH₂ --) and the like, ofwhich ethynylene group is preferred.

Illustrative examples of the group represented by the formula--(CH₂)_(m) Z(CH₂)_(n) -- include --OCH₂ --, --CH₂ O--, --COCH₂, --CH₂CO--, --NHCH₂ --, --CH₂ NH--, --N(CH₃)CH₂ --, --CH₂ N(CH₃)--, --N(CH₂CH₃)CH₂ --, --CH₂ N(CH₂ CH₃)--, --NHC(CH₃)₂ (CH₂)₅ --, --CH₂ OCH₂ --,--CH₂ COCH₂ --, --CH₂ NHCH₂ --, --CH₂ N(CH₃)CH₂ --, --CH₂ NH(CH₂ CH₃)CH₂--, --CH₂ NHC(CH₃)₂ (CH₂)₅ --, --(CH₂)₂ O--, --(CH₂)₃ O--, --(CH₂)₄ O--,--(CH₂)₅ O-- and the like, of which --CH₂ O--, --CH₂ NH-- and --COCH₂are preferred, and --CH₂ O-- is particularly preferred.

Illustrative examples of the group represented by the formula--(CH₂)_(m) Z(CH₂)_(n) CR₄ = include --OCH₂ CH=, --OCH₂ C(CH₃)=, --OCH₂C(CH₂ CH₃)=, --OCH₂ CF=, --OCH₂ CCl=, --CH₂ OCH=, --COCH₂ CH=, --CH₂COCH=, --NHCH₂ CH=, --CH₂ NHCH=, --N(CH₃)CH₂ CH=, --CH₂ N(CH₃)CH=,--N(CH₂ CH₃)CH₂ CH=, --CH₂ N(CH₂ CH₃)CH=, --CH₂ OCH₂ CH=, --CH₂ COCH₂CH=, --CH₂ NHCH=, --CH₂ CH(CH₃)CH₂ CH=, --CH₂ N(CH₂ CH₃)CH₂ CH=, --CH₂NHC(CH₃)₂ CH=, --(CH₂)₂ OCH₂ CH=, --(CH₂)₃ OCH₂ CH= and the like, ofwhich --OCH₂ CH=, --OCH₂ C(CH₃)=, --OCH₂ CF= and --CH₂ OCH₂ CH= arepreferred, and --OCH₂ CF= is particularly preferred.

Examples of the "substituent" of the lower alkyl group which may have asubstituent of R₃ include a hydroxyl group, a lower alkoxy group, anamino group, a mono- or di-lower alkylamino group, a carboxyl group, alower alkoxycarbonyl group, a carbamoyl group, a mono- or di-loweralkylcarbamoyl group and an aryl group, and these substituents may besubstituted at optional positions.

The following describes the substituents in detail.

The "lower alkoxy group" and "halogen atom" are as defined in theforegoing.

The "aryl group" means a carbocyclic aryl group, and its illustrativeexamples include phenyl, tolyl, xylyl, biphenyl, naphthyl, anthryl,phenanthryl and the like, of which phenyl is particularly preferred.

The "mono- or di-lower alkylamino group" is a group in which an aminogroup is substituted with one or two of the aforementioned lower alkylgroups, and its illustrative examples include mono-lower alkylaminogroups such as methylamino, ethylamino, propylamino, isopropylamino,butylamino, isobutylamino, sec-butylamino, tert-butylamino,pentyl(amyl)amino, isopentylamino, neopentylamino, tert-pentylamino andthe like and di-lower alkylamino groups such as dimethylamino,ethylmethylamino, diethylamino, dipropylamino, diisopropylamino,dibutylamino, diisobutylamino and the like, of which methylamino,ethylamino, dimethylamino and diethylamino groups are preferred, and adimethylamino group is particularly preferred.

The "lower alkoxycarbonyl group" means a carboxyl group which issubstituted with one of the aforementioned lower alkoxy groups, and itsillustrative examples include methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxy(amyloxy)carbonyl,isopentyloxycarbonyl, tert-pentyloxycarbonyl, neopentyloxycarbonyl,2-methylbutoxycarbonyl, 1,2-dimethylpropoxycarbonyl,1-ethylpropoxycarbonyl, hexyloxycarbonyl and the like, of whichmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and isopropoxycarbonylgroups are preferred, and ethoxycarbonyl group is particularlypreferred.

The "mono- or di-lower alkylcarbamoyl group" is a carbamoyl group whichis substituted with one or two of the aforementioned lower alkyl groups,and its illustrative examples include mono-lower alkylcarbamoyl groupssuch as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl,isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl,sec-butylcarbamoyl, tert-butylcarbamoyl, pentyl(amyl)carbamoyl,isopentylcarbamoyl, neopentylcarbamoyl, tert-pentylcarbamoyl and thelike and di-lower alkylcarbamoyl groups such as dimethylcarbamoyl,ethylmethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl,diisopropylcarbamoyl, dibutylcarbamoyl, diisobutylcarbamoyl and thelike, of which methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl anddiethylcarbamoyl are preferred.

Depending on the type of groups, the compound (I) of the presentinvention may have an asymmetric carbon atom and a double bond. Inconsequence, various isomers such as optical isomers, geometricalisomers (cis-form and trans-form) and the like, either in isolated formsor as mixtures, are all included in the compound (I) of the presentinvention.

The compound (I) of the present invention may form acid addition saltsor salts with bases. These salts are also included in the compound ofthe present invention. Examples of such salts include acid additionsalts with inorganic acids such as hydrochloric acid, hydrobromic acid,hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, organic acids such as formic acid, acetic acid, propionic acid,oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid,lactic acid, malic acid, tartaric acid, citric acid, methanesulfonicacid, ethanesulfonic acid and the like and acidic amino acids such asaspartic acid, glutamic acid and the like, and salts with inorganicbases such as sodium, potassium, magnesium, calcium, aluminum and thelike and organic bases such as methylamine, ethylamine,monoethanolamine, diethanolamine, triethanolamine, cyclohexylamine,lysine, ornithine and the like.

Also, the compound (I) of the present invention and salts thereof may beisolated as hydrates, various solvates such as ethanol solvate and thelike or polymorphic forms thereof, and these various hydrates, solvatesand polymorphic forms are also included in the compound of the presentinvention.

(Production Method)

The compound of the present invention represented by the general formula(I) can be synthesized, for example, by the following methods, thoughproduction methods of the compound of the present invention are notrestricted thereby. In addition, since novel intermediates are alsoincluded in the present invention, their production methods are alsodescribed in detail.

First production method (Synthesis of intermediate) ##STR7## (In theabove formulae, R is a lower alkyl group and M is a leaving group.)

As the leaving group, halogen atoms such as chlorine, bromine, iodineand the like and mesyloxy, tosyloxy and the like can be exemplified.

Method A: In this method, 3-quinuclidinone (II) is subjected to theWittig reaction (first step) to effect formation of a complex withborane (second step) which is isomerized (third step) to give an ester(V), the ester is subjected to a reduction reaction to give an alcohol(VII) (fourth step) and then the hydroxyl group of the alcohol (VII) isconverted into a leaving group (fifth step), thereby obtaining aquinuclidine compound (VIII) which is a starting compound for thecompound of the present invention. The order of the first step and thesecond step may be changed.

The Wittig reaction is carried out in the conventional way.Illustratively, the reaction is effected by stirring 3-quinuclidinone(II) and the reaction-corresponding amount, preferably 1 to 2equivalents, of a Wittig reaction agent (for example, a phosphonic acidderivative such as trimethyl 2-phosphonoacetate, triethyl2-phosphonoacetate, triisopropyl 2-phosphonoacetate, triethyl2-fluoro-2-phosphonoacetate (when R₄ =fluorine atom), triethyl2-methyl-2-phosphonopropionate (when R₄ =methyl group) or the like) atroom temperature or with heating in an organic solvent inert to thereaction (e.g., methanol, ethanol, isopropanol, tetrahydrofuran (THF),dioxane, diethyl ether, dimethoxyethane, toluene, benzene or the like)in the presence of a base (e.g., sodium alkoxide such as sodiummethoxide, sodium ethoxide or the like, metal hydride such as sodiumhydride, lithium hydride, potassium hydride or the like, sodiumhydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate,sodium bicarbonate, sodium carbonate, or alkyl lithium such as n-butyllithium or the like). In addition to the just described Wittig reactionagents, various stable ylide compounds such astriphenylphosphoranylidenacetic acid methyl ester,triphenylphosphoranylidenacetic acid ethyl ester and the like can alsobe used.

In this production method, 3-quinuclidinone hydrochloride may be usedinstead of 3-quinuclidinone (II). In that case, it is necessary to addthe aforementioned base in an increased amount equivalent to hydrogenchloride.

The borane complex formation reaction is carried out by stirring thequinuclidine compound (III) and the reaction-corresponding amount ofborane in the aforementioned organic solvent with ice-cooling.

The isomerization reaction is carried out by stirring the ester (IV) andthe reaction-corresponding amount of the aforementioned base in analcohol such as methanol, ethanol, isopropanol or the like at roomtemperature or with heating, preferably from room temperature to 50° C.

For example, when R is a methyl group and R₄ is a hydrogen atom, thedouble bond-based geometrical isomer ratio is changed from Z/E=1/1 to10/1 after isomerization. The geometrical isomers are converted intoalcohol by the subsequent reduction reaction (described hereinafter) andthen separated easily by silica gel chromatography or the like.

The reduction reaction is carried out by stirring the ester (V) in thepresence of the reaction-corresponding amount of a reducing agent (metalhydride such as diisobutylaluminum hydride, lithium aluminum hydride,sodium bis(2-methoxyethoxy)aluminum hydride or the like) in an organicsolvent inert to the reaction, such as toluene, THF, diethyl ether,hexane or the like at cooling temperature to room temperature,preferably at -78° C. to 0° C.

The leaving group conversion reaction is carried out by addingmethanesulfonyl chloride and lithium chloride to the alcohol (VII)obtained in the above reduction reaction and stirring the mixture in thepresence of an amine base (triethylamine or the like) in a solvent inertto the reaction, such as methylene chloride, dimethylformamide (DMF),THF, dioxane, diethyl ether or the like at room temperature.

Method B: In this process, the starting material is subjected to Wittigreaction (first step), isomerized (second step) and then made into acomplex with borane (third step), thereby obtaining the ester (V) whichis subsequently converted into the quinuclidine compound (VIII) in thesame manner as the case of Method A.

Each of these steps is as described in Method A.

Second production method ##STR8##

In this production method, a borane-added form (X) of the compound ofthe present invention is obtained by subjecting the quinuclidinecompound (VIII) and a hydroxy compound (IX) to alkylation reaction. Thealkylation reaction is carried out by stirring the quinuclidine compound(VIII) and the reaction-corresponding amount of a hydroxy compound (IX)in the presence of a base (potassium carbonate, sodium carbonate, sodiumhydroxide, potassium hydroxide, sodium hydride or alkyl lithium such asn-butyl lithium, or the like) in an organic solvent inert to thereaction, such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO),THF, dioxane, diethyl ether, dimethoxyethane, acetone, acetonitrile orthe like at room temperature.

Third production method ##STR9##

(In the above formulae, R_(3a) and R_(3b) are different from each otherand each represents a group of R₃ other than a hydrogen atom.)

In this production method, the compound of the present invention isobtained by the elimination of borane, alkylation reaction when X is NHand conversion reaction of the substituent.

Elimination of borane: This is carried out by stirring correspondingborane complex (X, XI or XII) at room temperature or with heating, inthe presence of an acid (an inorganic acid such as hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or thelike, or an organic acid such as a carboxylic acid (e.g., acetic acid,oxalic acid or the like) or an organic sulfonic acid (e.g.,methanesulfonic acid, p-toluenesulfonic acid or the like) in an organicsolvent inert to the reaction, such as an alcohol (e.g., methanol,ethanol, isopropanol or the like), THF, diethyl ether, DMF or the like.Thereafter, the free-form compound of the present invention (Ia, Ib orIc) can be obtained by stirring at room temperature in the presence of abase (potassium carbonate aqueous solution, sodium bicarbonate aqueoussolution, sodium hydroxide aqueous solution or the like).

Alkylation: This is carried out by stirring the borane complex (X) inwhich X is NH and the reaction-corresponding amount of an alkylatingagent (a halogenoalkyl or the like) in the presence of a base (sodiumhydride, potassium hydride, lithium hydride, sodium hydroxide, potassiumhydroxide, potassium carbonate or alkyl lithium such as n-butyl lithium,methyl lithium, t-butyl lithium or the like) in an organic solvent inertto the reaction, such as DMF, DMSO, THF, dioxane, diethyl ether,dimethoxyethane, acetonitrile or the like at cooling temperature to roomtemperature, thereby obtaining the compound (XI) in which R₃ is a loweralkyl group which may have an aryl group, a hydroxyl group, a loweralkoxy group, an amino group, a mono- or di-lower alkylamino group, acarboxy group, a lower alkoxycarbonyl group, a carbamoyl group or amono- or di-lower alkylcarbamoyl group as a substituent.

The substituent conversion reaction, for example, the reaction from anamino-lower alkyl group to a mono- or di-lower alkylamino-lower alkylgroup or from a carbamoyl group to a mono- or di-lower alkylcarbamoylgroup, can be effected by a method similar to the above alkylationreaction.

Also, the carbazole compound (XI) or (XII) can be synthesized directlyfrom the intermediate (VIII) by the second production method using thecompound (IX) in which X is NR₃.

Fourth production method ##STR10##

The compound (Id) of the present invention is produced by theelimination of borane (deprotection) from an ether compound (XV) whichis obtained by the alkylation of a borane-(3-quinuclidinol) complex(XIV) in the presence of a base.

The alkylation reaction can be effected by the same method of the secondproduction method, and elimination of borane can be effected by the samemethod of the third production method.

In this production method, a compound of the present inventionrepresented by (Ie) can be produced by carrying out the same reactionusing a borane- 3-(2-hydroxyethylidene)quinuclidine! complex (VII)instead of the alcohol (XIV) of the material compound.

Fifth production method ##STR11##

The compound (If) of the present invention is produced by a reductivecondensation reaction of an aromatic aldehyde (XVI) with3-aminoquinuclidine (XVII). This reaction is carried out by using thecompound (XVI) and 3-aminoquinuclidine (XVII) in equivalent molar ratioor either one of them in an excess amount, and stirring them at roomtemperature or with heating, in an organic solvent inert to thereaction; such as dichloromethane, THF, methanol, ethanol, benzene orthe like, water, or a mixture solvent thereof, in the presence of areducing agent, or by subjecting the compound (VI) and thereaction-corresponding amount of 3-aminoquinuclidine (VII) to acondensation reaction without solvent or in a solvent such as benzene,toluene or the like while removing water under azeotropic condition orin the presence of a drying agent, thereby synthesizing a Schiff base,and then carrying out the reduction reaction in a solvent such asethanol, methanol or the like in the presence of a reducing agent.

Preferred examples of the reducing agent to be used in this reactioninclude metal hydrides such as sodium borohydride, sodiumtriacetoxyborohydride, sodium cyanoborohydride and the like. Acidcatalysts such as hydrochloric acid, acetic acid and the like may alsobe used.

When n is 0 in the compound (If) of the present invention, a reductivecondensation reaction of the amine compound (XVIII) with3-quinuclidinone (II) may be used as an alternative method. The reactionconditions, solvents and reducing agents can be set in the same manneras described above.

Sixth production method ##STR12## (In the above formulae, R is a loweralkyl group and D is a chlorine atom or a bromine atom.)

The compound (Ig) of the present invention is produced by the followingmethod using an aldehyde (XIX) as the material compound. This productionmethod is effected by allowing a dihalogenoolefin (XX) obtained by theWittig reaction (first step) to react with 2 equivalents of an organiclithium reagent, and then allowing the resulting lithium acetylide (XXI)to react with 3-quinuclidinone (second step).

Preferably, the Wittig reaction may be carried out by using a Wittigreaction agent prepared by mixing carbon tetrabromide, zinc (dust) andtriarylphosphine such as triphenylphosphine or the like indichloromethane, and allowing the agent to react with the aldehyde(XIX).

Examples of the organic lithium reagent to be used in the second stepinclude n-butyl lithium, methyl lithium, sec-butyl lithium, t-butyllithium and the like, and examples of the reaction solvent includeethers such as THF, diethyl ether, dimethoxyethane and the like andinert solvents such as cyclohexane, hexane, pentane and the like.Preferably, the compound (Ig) of the present invention can be obtainedwith high yield by a method in which n-butyl lithium (2 equivalents) isadded under cooling (--78° to 0° C.) to THF solution of the compound(XX), and the mixture is warmed to room temperature, cooled again andthen allowed to react with 3-quinuclidinone added.

Seventh production method ##STR13##

The compound (Ih) of the present invention is produced by allowing ametal enolate, which is formed by the reaction of a methyl aryl ketone(XXII) with a base, to undergo an aldol reaction with 3-quinuclidinone.As the base, metal amides such as lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide and thelike are used preferably. When the compound (XXII) is a phenothiazinederivative which has a lower alkyl substituent at the 10-position, thesame mol equivalent of the base is required based on the compound(XXII), while two equivalents of the base is required based on theketone (XXII) in the case of a phenothiazine derivative which has nosubstituent at the 10-position. Examples of the reaction solvent includeethers such as THF, diethyl ether, dimethoxyethane and the like whichare generally used in the aldol reaction of metal enolate.

As an alternative method, various inorganic metal salts such as zincchloride, magnesium chloride, titanium tetrachloride and the like areadded to the lithium enolate or potassium enolate which is formed whenthe aforementioned base is used, and then the aldol reaction is carriedout by adding 3-quinuclidinone.

The compound (I) of the present invention obtained in this manner isisolated and purified as its free form or as a salt thereof, a hydratethereof, a solvate thereof or a polymorphic form thereof. Also, salts ofthe compound (I) of the present invention can be produced by subjectingthe compound to usual salt forming reactions.

The isolation and purification are carried out by employing usualchemical operations such as extraction, concentration, distillation,crystallization, filtration, recrystallization, various chromatographictechniques and the like.

Various isomers can be separated by selecting appropriate materialcompounds or making use of differences in physical properties betweenisomers. For example, optical isomers can be separated intostereochemically pure isomers by selecting an appropriate materialcompound or by racemic resolution of racemic compounds (for example, amethod in which such compounds are converted into diastereomer saltswith general optically active acids or bases and then subjected tooptical resolution).

In addition to the compounds described in the Examples, the followingcompounds can be obtained without requiring special experiments inaccordance with the aforementioned production methods, the productionmethods described in the Examples and their modifications known to thoseskilled in the art.

3-(10-Propylphenothiazin-3-ylmethoxy)quinuclidine,

3-(10-Isobutylphenothiazin-3-ylmethoxy)quinuclidine,

3-(10-tert-Butylphenothiazin-3-ylmethoxy)quinuclidine,

3-(10-Pentylphenothiazin-3-ylmethoxy)quinuclidine,

3-(10-Hexylphenothiazin-3-ylmethoxy)quinuclidine,

(Z)-3- 2- 9-(3-aminopropyl)carbazol-2-yloxy!ethylidene!quinuclidine,

(E)-3- 2- 9-(3-aminopropyl)carbazol-2-yloxy!ethylidene!quinuclidine,

(Z)-3- 2- 9-(4-aminobutyl)carbazol-2-yloxy!ethylidene!quinuclidine,

(E)-3- 2- 9-(4-aminobutyl)carbazol-2-yloxy!ethylidene!quinuclidine,

(Z)-3- 2- 9-2-(methylamino)ethyl!carbazol-2-yloxy!ethylidene!quinuclidine,

(E)-3- 2- 9-2-(methylamino)ethyl!carbazol-2-yloxy!ethylidene!quinuclidine,

(Z)-3- 2- 9-2-(ethylamino)ethyl!carbazol-2-yloxy!ethylidene!quinuclidine,

(E)-3- 2- 9-2-(ethylamino)ethyl!carbazol-2-yloxy!ethylidene!quinuclidine,

(Z)-3- 2- 9-3-(methylamino)propyl!carbazol-2-yloxy!ethylidene!quinuclidine

(E)-3- 2- 9-3-(methylamino)propyl!carbazol-2-yloxy!ethylidene!quinuclidine

(Z)-3- 2- 9-3-(ethylamino)propyl!carbazol-2-yloxy!ethylidene!quinuclidine,

(E)-3- 2- 9-3-(ethylamino)propyl!carbazol-2-yloxy!ethylidene!quinuclidine,

(Z)-3- 2- 9-3-(diethylamino)propyl!carbazol-2-yloxy!ethylidene!quinuclidine.

(E)-3- 2-(carbazol-2-yloxy)-1-chloroethylidene!quinuclidine

(Z)-3- 2-(carbazol-2-yloxy)-1-ethylethylidene!quinuclidine

(Z)-3- 2-(carbazol-2-yloxy)-1-propylethylidene!quinuclidine

(E)-3- 2-(carbazol-2-ylthio)-1-fluoroethylidene!quinuclidine

(Z)-3- 2-(carbazol-2-ylthio)-1-methylethylidene!quinuclidine

(E)-3- 2-(dibenzofuran-3-yloxy)-1-fluoroethylidene!quinuclidine

INDUSTRIAL APPLICABILITY

The compound (I) of the present invention, a pharmaceutically acceptablesalt thereof, a hydrate-thereof or a solvate thereof have excellentsqualene synthase inhibiting activity and excellent cholesterolbiosynthesis inhibiting action in the living body based on thisactivity. Also, since the compound is effective even in experiments inwhich human cultured cells are used, it is useful for the prevention ortreatment of arteriosclerosis, aneurysm, ischemic heart diseases such asmyocardial infarction, angina pectoris and the like and cerebralarteriosclerotic diseases such as cerebral infarction and the like,induced by the action of cholesterol in human and warm-blooded animals,particularly in human.

In addition, since the compound of the present invention selectivelyinhibits squalene synthase which is an enzyme located at the middlestage of the cholesterol biosynthesis system, it shows extremely loweredside effects or shows no side effects which are common in inhibitors ofenzymes located at the early stage or late stage of the cholesterolbiosynthesis system, such as inhibition of the synthesis of importantmetabolic products such as dolichol, ubiquinone, isopentenyl tRNA,p21Ras, low molecular weight G protein and the like and generation ofhepatic cytotoxicity (myopathy) caused by the accumulation of toxicsubstances such as desmosterol.

The squalene synthase inhibiting action and cholesterol biosynthesisinhibiting action of the compound of the present invention have beenconfirmed by the following methods.

I. Test methods

A. Test on human squalene synthase inhibition

(1) Preparation of squalene synthase from human hepatoma cells

Human hepatoma cells (HepG2 cells) were cultured using DMEM containing10% FBS until a single layer was formed, and then the medium wasreplaced by DMEM supplemented with 10% human lipoprotein deficient serum(LPDS) to carry out 24 hours of culturing. The cells were washed twicewith PBS, collected using a Rubber Policeman and subjected tocentrifugation. The resulting precipitate was homogenized in fivevolumes of 50 mM Hepes buffer (pH 7.5) containing 5 mM EDTA andcentrifuged at 20,000×g for 15 minutes. The supernatant was againsubjected to the same centrifugation. The supernatant was subjected to 1hour of centrifugation at 100,000×g, and the microsomes obtained weresuspended in the same buffer and used in the test as a HepG2 squalenesynthase fraction.

(2) Measurement of squalene synthase inhibiting activity

A dimethyl sulfoxide solution of each drug to be tested was added to asolution of the squalene synthase fraction prepared above (protein 10ng, 50 mM Hepes buffer (pH 7.5)), 11 mM NaF, 5.5 mM MgCl₂, 3 mM DTT, 1mM NADPH, 1 mM pyrophosphate and 2.5 μM ³ H-FPP, and the mixture wasadjusted to a total volume of 0.2 ml and shaken at 30° C. for 20 minutesto effect the reaction. The reaction was terminated by adding 100 μl of20% potassium hydroxide-50% ethanol solution, and the reaction solutionwas heated at 65° C. for 30 minutes. The un-saponified material wasextracted with petroleum ether, and 1/3 volume thereof was subjected tomeasurement by a liquid scintillation counter. The ³ H radioactivity ofthe un-saponified material was regarded as products down stream ofsqualene in the cholesterol biosynthesis system, and the squalenesynthase inhibiting action was calculated by comparing ³ Hradioactivities of the test group and control group.

In addition, concentration of each compound of the present invention toinhibit 50% of squalene synthase (IC₅₀ value) was obtained bycalculation.

B. Inhibition test of rat squalene synthase

(1) Preparation of rat squalene synthase

An male SD rat loaded with 3% colestyramine feed for 2 weeks wassacrificed by bleeding to excise the liver which was subsequentlyhomogenized in five volumes of 50 mM Hepes buffer (pH 7.5) containing 5mM EDTA and centrifuged at 20,000×g for 15 minutes. The supernatant wasagain subjected to the same centrifugation. The supernatant was furthersubjected to 1 hour of centrifugation at 100,000×g, and the resultingmicrosomes were suspended in the same buffer and used in the test as asqualene synthase fraction.

(2) Squalene synthase inhibiting activity was measured by the samemethod of the above item A (2).

C. Cholesterol lowering action in hamster

Male golden hamsters (130 to 150 g) which have been treated by reversingnight and day since 12 or more days before the commencement ofadministration were divided into groups 4 days before the administrationin such a manner that the cholesterol value became the same among thegroups. Each drug was prepared as a 0.5% methyl cellulose solution andadministered by force in a dosage of 50 mg/kg. In this case, the liquidvolume was 10 ml/kg.

The administration was carried out continuously for 4 days at aroundA.M. 11:00 under satiated condition and then on the fifth day after 16hours of fasting. After 2 hours of the final administration, bloodsamples were collected from the abdominal vena cava under diethyl etheranesthesia and their cholesterol values were measured using an automaticanalyzer (Hitachi 736).

II. Test results

The measured results of each compound of the present invention are shownin the following.

(1) Results of the inhibition test on squalene synthase derived fromhuman hepatoma cell

The IC₅₀ value of squalene synthase inhibiting activity was calculatedby the aforementioned test method (A), with the results shown in Table1.

                  TABLE 1                                                         ______________________________________                                               Compound                                                                              IC.sub.50 value                                                ______________________________________                                               Example 1                                                                             79 nM                                                                 Example 2                                                                             59 nM                                                                 Example 17                                                                            85 nM                                                          ______________________________________                                    

As the result, each compound of the present invention showed strongactivity to inhibit squalene synthase prepared from human hepatomacells.

In addition, the compounds of the present invention showed clearinhibiting action also in the rat squalene synthase inhibition testwithin the concentration range of approximately from 0.01 to 25 μM.

(2) Cholesterol lowering action in hamster

The cholesterol lowering action was measured by the aforementioned testmethod (C), with the results on the lowering ratio shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Compound     Lowering ratio (%)                                               ______________________________________                                        Example 1    57                                                               Example 2    39                                                               Example 17   46                                                               ______________________________________                                    

As the result, the compounds of the present invention showed strongaction to lower cholesterol level.

Thus, the compounds of the present invention showed strong activity toinhibit human squalene synthase and strong action to lower cholesterollevel in hamster. In consequence, the compounds of the present inventionare useful for the treatment or prevention of various diseases inducedby the action of cholesterol (arteriosclerosis, aneurysm, ischemic heartdiseases such as myocardial infarction, angina pectoris and the like andcerebral arteriosclerotic diseases such as cerebral infarction and thelike).

The pharmaceutical composition which contains one or two or more of thecompound (I) of the present invention, pharmaceutically acceptable saltsthereof, hydrates thereof and solvates thereof as the active ingredientis prepared into tablets, powders, fine powders, granules, capsules,pills, solutions, injections, suppositories, ointments, adhesivepreparations and the like using generally used pharmaceutical carriers,excipients and other additives and administered orally (includingsublingual administration) or parenterally.

Clinical dose of the compound (I) of the present invention in human isappropriately decided by taking symptoms, age, sex and the like of eachpatient to be treated into consideration, but the compound may beadministered orally generally within the range of from 10 mg to 500 mg,preferably from 100 mg to 500 mg, per day per adult, by dividing thedaily dose into one to several doses per day, or within the range offrom 1 mg to 100 mg, preferably from 10 mg to 100 mg, per day per adult,by intravenous administration by dividing the daily dose into one toseveral doses per day, or by continuous intravenous administrationwithin the range of from 1 hour to 24 hours per day. As a matter ofcourse, since the dosage varies under various conditions, a smallerdosage than the above range may be sufficient enough in some cases.

The solid composition for use in the oral administration according tothe present invention is used in the form of tablets, powders, granulesand the like. In such a solid composition, one or more active substancesare mixed with at least one inert diluent such as lactose, mannitol,glucose, hydroxypropylcellulose, microcrystalline cellulose, starch,polyvinyl pyrrolidone or aluminum magnesium metasilicate. In theconventional way, the composition may contain additives other than theinert diluent, such as lubricants (e.g., magnesium stearate or thelike), disintegrating agents (e.g., calcium cellulose glycolate or thelike), stabilizing agents (e.g., lactose or the like), andsolubilization assisting agent (e.g., glutamic acid, aspartic acid orthe like). If necessary, tablets or pills may be coated with a film of agastric soluble or enteric soluble substance such as sucrose, gelatin,hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or thelike.

The liquid composition for oral administration includes pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, elixirs and thelike and contains a generally used inert diluent such as purified wateror ethanol. In addition to the inert diluent, this composition may alsocontain auxiliary agents such as a solubilizing or solubilizationassisting agent, a moistening agent, a suspending agent and the like, aswell as sweeteners, flavors, aromas and antiseptics.

The injections for parenteral administration includes aseptic aqueous ornon-aqueous solutions, suspensions and emulsions. Examples of theaqueous solutions and suspensions include distilled water for injectionuse and physiological saline. Examples of the non-aqueous solutions andsuspensions include propylene glycol, polyethylene glycol, plant oils(e.g., olive oil or the like), alcohols (e.g., ethyl alcohol or thelike), polysorbate 80 (trade name) and the like. Such a composition mayfurther contain additive agents such as a tonicity agent, an antiseptic,a moistening agent, an emulsifying agent, a dispersing agent, astabilizing agent (e.g., lactose) and a solubilizing or solubilizationassisting agent. These compositions are sterilized by filtration througha bacteria retaining filter, blending of a germicide or irradiation.Alternatively, they may be used by firstly making into sterile solidcompositions and dissolving them in sterile water or a sterile solventfor injection use prior to their use.

BEST MODE OF CARRYING OUT THE INVENTION

The following illustratively describes the present invention withreference to Examples though the present invention is not restrictedthereby. In this connection, novel material compounds to be used in theExamples are also described as Reference Examples.

Reference Example 1

Borane- ethyl fluoro-(3-quinuclidinylidene)acetate! complex

Sodium hydride (60 wt. %, 83.6 g, 2.09 mol) was added to a mixture oftriethyl 2-fluoro-2-phosphonoacetate (506 g, 2.09 mol) and THF (3.0 l)with ice-cooling, and the mixture was stirred for 2 hours. A THF (600ml) solution of 3-quinuclidinone (238 g, 1.90 mol) was added and themixture was stirred at room temperature for 5 days. Water (500 ml) wasadded to the reaction mixture and the mixture was concentrated under areduced pressure. Water (2.5 l) was added to the residue, and then thereaction product was extracted with chloroform (1.5 l×2). The extractwas washed with saturated sodium chloride aqueous solution, dried overanhydrous magnesium sulfate and then concentrated under a reducedpressure. THF (1.0 l) was added to the resulting yellow oily material,and then a borane-THF complex (1.0M THF solution, 2.1 l, 2.1 mol) wasadded dropwise with ice-cooling spending 2.5 hours. After additional 0.5hour of stirring, water (400 ml) was added to the reaction mixture andthe mixture was concentrated under a reduced pressure. Ethyl acetate wasadded to the resulting residue, the mixture was washed with water andsaturated sodium chloride aqueous solution in that order, dried overanhydrous magnesium sulfate, and then concentrated under a reducedpressure. The resulting residue was washed with hexane (400 ml) anddried under a reduced pressure. Ethanol (2.8 l) was added to theresulting brown solid (402 g) and then, while heating at 50° C., sodiumhydride (60 wt. %, 4.24 g, 106 mmol) was added, and the mixture wasstirred for 7 hours. After spontaneous cooling, acetic acid (5.4 ml) wasadded to the reaction mixture, and the mixture was concentrated under areduced pressure. Ethyl acetate was added to the residue, and themixture was washed with water and saturated sodium chloride aqueoussolution in that order, dried over anhydrous magnesium sulfate, and thenconcentrated under a reduced pressure. Ethanol (1.2 l) was added to theresulting brown solid, and the mixture was stirred for 20 minutes. Theinsoluble matter was removed by filtration and then the resultingfiltrate was concentrated under a reduced pressure to give the titlecompound (304 g, E/Z mixture) as a brown oil.

Mass spectrometry data (m/z): 213 (M⁺)

Reference Example 2

Borane- (E)-3-(1-fluoro-2-hydroxyethylidene)quinuclidine! complex

A mixture of sodium bis(2-methoxyethoxy)aluminum hydride (70 wt. %toluene solution, 425 g, 1.47 mol) and toluene (800 ml) was addeddropwise (2.5 hours) to a mixture of borane- ethylfluoro-(3-quinuclidinylidene)acetate! complex (304 g, E/Z mixture) andtoluene (800 ml) while keeping the inner temperature at -45° to -35° C.,and the mixture was stirred for additional 1 hour. A 2N sodium hydroxideaqueous solution (1.5 l) was added to the reaction mixture, and themixture was stirred at room temperature for 1 hour. The insoluble matterwas removed by filtration and the reaction product was extracted withethyl acetate. The extract was washed with saturated sodium chlorideaqueous solution, dried over anhydrous magnesium sulfate, and thenconcentrated under a reduced pressure. The resulting residue waspurified by silica gel column chromatography (eluent; ethylacetate:hexane =25:75 then 35:65) to give the title compound (115 g,0.62 mol, 46%) as colorless crystals.

Nuclear magnetic resonance spectrum (CDCl₁, TMS internal standard)

δ: 1.30-1.80 (3H, br), 1.80-1.90 (4H, m), 1.99 (1H, m), 3.00-3.15 (4H,m), 3.67 (2H, s), 4.13 (2H, m).

Reference Example 3

Borane- (E)-3-(2-chloro-1-fluoroethylidene)quinuclidine! complex

Lithium chloride (55.1 g, 1.3 mol) and methanesulfonyl chloride (40 ml,520 mmol) were added in that order to a solution of borane-(E)-3-(1-fluoro-2-hydroxyethylidene)quinuclidine! complex (80.1 g, 433mmol), dichloromethane (650 ml) and triethylamine (120 ml, 866 mmol)with ice-cooling, the mixture was stirred for 1 hour and then at roomtemperature for 5 hours. The reaction mixture was concentrated under areduced pressure, water was added to the residue, and the reactionproduct was extracted with ethyl acetate. The extract was washed withsaturated sodium chloride aqueous solution, dried over anhydrousmagnesium sulfate, and then concentrated under a reduced pressure togive the title compound (75.5 g, 371 mmol, 86%) as colorless crystals.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.30-1.80 (3H, m), 1.80-1.95 (5H, m), 3.00-3.15 (4H, m), 3.64 (2H,s), 4.03 (2H, d).

Reference Example 4

Borane- (E)-3- 2-(carbazol-2-yloxy)-1-fluoroethylidene!quinuclidine!complex

Potassium carbonate (97 g, 700 mmol) was added to a mixture of borane-(E)-3-(2-chloro-1-fluoroethylidene)quinuclidine! complex (75.3 g, 370mmol), 2-hydroxycarbazole (64.5 g, 352 mmol) and DMF (400 ml), and themixture was stirred at room temperature for 8.5 hours. The reactionmixture was poured into water (2.0 l) and the mixture was stirred for 1hour. The insoluble matter was collected by filtration, washed withwater, methanol and diethyl ether, and then dried under a reducedpressure. By recrystallizing the resulting crystals from ethyl acetate,the title compound (107.0 g, 306 mmol, 87%) was obtained.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.09 (3H, brs), 1.55-1.92 (4H, m), 2.47-2.55 (1H, m), 2.85-3.05 (4H,m), 3.64 (2H, d, J=3 Hz), 4.72 (2H, d, J=21 Hz); 6.84 (1H, dd, J=1 Hz, 9Hz), 7.03-7.50 (4H, m), 7.95 (1H, s), 8.04 (1H, s).

The compounds of Reference Examples 5 and 6 were obtained in the samemanner as in Reference Examples 1 to 4.

Reference Example 5

Borane- (Z)-3- 2-(carbazol-2-yloxy)ethylidene!quinuclidine! complex

Material compounds: 3-quinuclidinone, trimethyl 2-phosphonoacetate,2-hydroxycarbazole

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.80-1.88 (2H, m), 1.93-2.02 (2H, m), 2.70-2.74 (1H, m), 3.22-3.32(4H, m), 4.14 (2H, s), 4.60 (2H, d, J=7 Hz), 5.74-5.76 (1H, m),6.76-6.80 (1H, m), 6.98-7.00 (1H, m), 7.10-7.14 (1H, m), 7.28-7.32 (1H,m), 7.62 (1H, d, J=8 Hz), 7.94-8.00 (2H, m).

Reference Example 6

Borane- (Z)-3- 2-(carbazol-2-yloxy)-1-methylethylidene!quinuclidine!complex

Material compounds: 3-quinuclidinone, trimethyl 2-phosphonopropionate,2-hydroxycarbazole

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.09 (3H, brs), 1.49 (3H, s), 1.65-1.87 (4H, m), 2.78-3.19 (5H, m),3.73 (2H, s), 3.99 (2H, s), 6.67-6.83 (1H, m), 7.09-7:43 (4H, m),7.68-8.05 (2H, m), 8.73 (1H, brs).

Reference Example 7

Borane- ethyl (Z)- 2-2-(3-quinuclidinylidene)ethoxy!carbazol-9-yl!acetate! complex

In an atmosphere of argon, sodium hydride (60 wt. %, 0.78 g, 19.6 mmol)was added at 0° C. to a mixture of borane- (Z)-3-2-(9-carbazol-2-yloxy)ethylidene!quinuclidine! complex (5.93 g, 17.8mmol) and DMF (35 ml), and the mixture was stirred for 30 minutes. Ethylbromoacetate (2.38 ml, 21.4 mmol) was added and the mixture was stirredfor 1 hour. The reaction mixture was concentrated under a reducedpressure, ethyl acetate and saturated sodium chloride aqueous solution(60 ml for each) were added to the resulting residue in that order, andthe reaction product was extracted with ethyl acetate. The extract wasdried over anhydrous magnesium sulfate and concentrated under a reducedpressure to give the title compound (7.40 g, 17.7 mmol, 99%) as brownoil.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 0.94 (3H, brs), 1.24 (3H, t, J=7 Hz), 1.76-1.98 (4H, m), 1.51-1.65(1H, m), 2.86-3.19 (4H, m), 3.78 (2H, s), 4.21 (2H, q, J=7 Hz), 4.54(2H, d, J=6 Hz), 4.93 (2H, s), 5.57-5.78 (1H, m), 6.79-6.88 (2H, m),7.21-7.34 (3H, m), 7.90-8.04 (2H, m).

Reference Example 8

Borane- (Z)-3- 2-9-(2-hydroxyethyl)carbazol-2-yloxy!ethylidene!quinuclidine! complex

In an atmosphere of argon, diisobutyl aluminum hydride (0.93M, 56.5 mltoluene solution, 52.5 mmol) was added at -78° C. to a mixture ofborane- ethyl (Z)- 2-2-(3-quinuclidinylidene)ethoxy!carbazol-9-yl!acetate! complex (7.33 g,17.5 mmol) and toluene (86 ml), and the mixture was stirred for 2 hours.Methanol (4.4 ml) and water (7.4 ml) were added in that order and themixture was stirred for 1 hour at room temperature. The insoluble matterwas removed by filtration and the resulting filtrate was concentratedunder a reduced pressure to give the title compound (5.92 g, 15.7 mmol,90%) as colorless crystals.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.24 (3H, brs), 1.76-1.98 (4H, m), 2.56-2.66 (1H, m), 2.97-3.15 (4H,m), 3.77 (2H, s), 4.04 (2H, t, J=5 Hz), 4.36-4.58 (4H, m), 5.57-5.78(1H, m), 6.77-6.95 (2H, m), 7.12-7.43 (3H, m), 7.90-8.03 (2H, m).

Reference Example 9

Borane- (Z)-3- 2-9-(2-aminoethyl)carbazol-2-yloxy!ethylidene!quinuclidine! complex

A mixture of borane- (Z)-3- 2-9-(2-hydroxyethyl)carbazol-2-yloxy!ethylidene!quinuclidine! complex(3.60 g, 9.57 mmol), THF (19 ml), phthalimide (1.83 g, 19.8 mmol),triphenylphosphine (3.26 g, 19.8 mmol) and diethyl azodicarboxylate(1.92 ml, 19.8 mmol) was stirred at room temperature for 14 hours. Thereaction mixture was concentrated under a reduced pressure, and theresulting residue was purified by silica gel column chromatography(eluent; chloroform:methanol=100:1). To a mixture thereof with ethanol(80 ml) was added hydrazine monohydrate (2 ml) at room temperature, andthe resulting mixture was heated under reflux for 8 hours. Theprecipitate was removed by filtration, and the filtrate was concentratedunder a reduced pressure. The resulting residue was purified by silicagel column chromatography (eluent; chloroform:methanol:17% aqueousammonia=100:3:0.3) to give the title compound (1.52 g, 4.05 mmol, 42.3%)as colorless crystals.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.48 (3H, brs), 1.79-2.01 (4H, m), 2.55-2.69 (1H, m), 2.88-3.19 (6H,m), 3.81 (2H, s), 4.35 (2H, t, J=6 Hz), 4.57 (2H, d, J=6 Hz), 6.61-6.76(1H, m), 6.80-6.94 (2H, m), 7.29-7.80 (3H, m), 7.92-8.04 (2H, m).

Reference Example 10

Borane- (Z)-3- 2-9-(2-methoxyethyl)carbazol-2-yloxy!ethylidene!quinuclidine! complex

In an atmosphere of argon, sodium hydride (60 wt. %, 0.19 g, 4.79 mmol)was added at 0° C. to a mixture of borane- (Z)-3- 2-9-(2-hydroxyethyl)carbazol-2-yloxy!ethylidene!quinuclidine! complex(1.20 g, 3.19 mmol) and DMF (16 ml), and the mixture was stirred for 30minutes. Methyl iodide (0.30 ml, 4.79 mmol) was added and the mixturewas stirred for 1 hour. The reaction mixture was concentrated under areduced pressure, ethyl acetate and saturated sodium chloride aqueoussolution (each 30 ml) were added to the resulting residue in that order,and then the reaction product was extracted with ethyl acetate. Theextract was dried over anhydrous magnesium sulfate and concentratedunder a reduced pressure to give the title compound (1.24 g, 3.18 mmol,100%) as colorless crystals.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 0.91 (3H, brs), 1.78-2.00 (4H, m), 2.52-2.63 (1H, m), 2.99-3.15 (4H,m), 3.30 (3H, s), 3.70 (4H, m), 4.19 (2H, t, J=5 Hz), 4.56 (2H, d, J=6Hz), 5.60-5.79 (1H, m), 5.60-5.79 (1H, m), 5.76-5.95 (2H, m), 7.15-7.41(3H, m), 7.89-8.05 (2H, m).

Reference Example 11

10-Ethyl-3-formylphenothiazine

N-Methylformanilide (5.35 ml, 43.6 mmol) and phosphorus oxychloride(4.06 ml, 43.6 mmol) were added at room temperature to a mixture of10-ethylphenothiazine (7.62 g, 33.5 mmol) and 1,2-dichlorobenzene (34ml), and the mixture was stirred at 100° C. for 24 hours. At roomtemperature, a sodium acetate aqueous solution (45 wt. %, 85 g) wasadded to the reaction mixture, which was subsequently concentrated undera reduced pressure. Ethyl acetate and water (each 300 ml) were added tothe resulting residue in that order and then the reaction product wasextracted with ethyl acetate. The extract was dried over anhydrousmagnesium sulfate and then concentrated under a reduced pressure. Theresulting residue was purified by silica gel column chromatography(eluent; hexane:ethyl acetate=5:1) to give the title compound (5.91 g,23.1 mmol, 69%) as yellow crystals.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.44 (3H, t, J=7 Hz), 3.96 (2H, q, J=7 Hz), 6.84-7.25 (5H, m),7.56-7.68 (2H, m), 9.78 (1H, s).

The compounds of Reference Examples 12 and 13 were obtained in the samemanner as in Reference Example 11.

Reference Example 12

10-Butyl-3-formylphenothiazine

Material compound: 10-butylphenothiazine

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 0.95 (3H, t, J=7 Hz), 1.26-1.89 (4H, m), 3.89 (2H, t, J=7 Hz),6.84-7.60 (7H, m), 9.78 (1H, s).

Reference Example 13

3-Formyl-10-(1-methylethyl)phenothiazine

Material compound: 10-(1-methylethyl)phenothiazine

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.68 (6H, d, J=7 Hz), 4.22-4.54 (1H, m), 6.57-7.66 (7H, m), 9.79 (1H,s).

Reference Example 14

3-Hydroxymethyl-10-methylphenothiazine

With ice-cooling, sodium borohydride (4.16 g, 110 mmol) was added to amixture of 3-formyl-10-methylphenothiazine (24.6 g, 102 mmol), THF (100ml) and ethanol (100 ml), the mixture was stirred for 10 minutes andthen at room temperature for 20 minutes. The solvent was evaporatedunder a reduced pressure, water and 2N hydrochloric acid were added tothe residue in that order, and then the reaction product was extractedwith ethyl acetate. The extract was washed with a saturated sodiumbicarbonate aqueous solution and saturated sodium chloride aqueoussolution in that order, dried over anhydrous magnesium sulfate, and thenconcentrated under a reduced pressure. By recrystallizing the resultingresidue from ethyl acetate-hexane, the title compound (18.9 g, 77.7mmol, 76%) was obtained as yellow crystals.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 3.37 (3H, s), 4.57 (2H, d, J=6 Hz), 6.73-7.52 (7H, m).

The compounds of Reference Examples 15 to 18 were obtained in the samemanner as in Reference Example 14.

Reference Example 15

10-Ethyl-3-hydroxymethylphenothiazine

Material compound: 10-ethyl-3-formylphenothiazine

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 3.37 (3H, m), 4.57 (2H, d, J=6 Hz), 6.73-7.52 (7H, m).

Reference Example 16

10-Butyl-3-hydroxymethylphenothiazine

Material compound: 10-butyl-3-formylphenothiazine

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 0.97 (3H, t, J=7 Hz), 1.20-1.87 (4H, m), 3.84 (2H, t, J=7 Hz), 4.56(2H, s), 6.57-7.34 (7H, m).

Reference Example 17

3-Hydroxymethyl-10-(1-methylethyl)phenothiazine

Material compound: 3-formyl-10-(1-methylethyl)phenothiazine

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.61 (6H, d, J=7 Hz), 4.12-4.43 (1H, m), 4.56 (2H, s), 6.57-7.25 (7H,m).

Reference Example 18

3-Hydroxymethyl-10-methylphenoxazine

Material compound: 3-formyl-10-methylphenoxazine

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 3.04 (3H, s), 4.52 (2H, s), 6.43-6.95 (7H, m).

Reference Example 19

3-Hydroxymethyl-10-methylphenothiazine-5-oxide

With ice-cooling, m-chloroperbenzoic acid (1.66 g, 9.6 mmol) was addedto a mixture of 3-hydroxymethyl-10-methylphenothiazine (1.94 g, 8.0mmol) and dichloromethane (30 ml), and the mixture was stirred for 1.5hours and then at room temperature for 1.5 hours. A saturated sodiumbicarbonate aqueous solution was added to the reaction mixture and thereaction product was extracted with chloroform. The extract was driedover anhydrous magnesium sulfate and then concentrated under a reducedpressure. The resulting residue was purified by silica gel columnchromatography (eluent; methanol:chloroform=3:97 then 10:90) to give thetitle compound (1.95 g, 7.52 mmol, 94%) as colorless crystals.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 2.33 (1H, t), 3.76 (3H, s), 4.79 (2H, d), 7.25 (1H, m), 7.35-7.90(2H, m), 7.60-7.65 (2H, m), 7.89 (1H, d), 7.92 (1H, m).

Reference Example 20

3-Hydroxymethyl-10-methylphenothiazine-5,5-dioxide

With ice-cooling, m-chloroperbenzoic acid (2.59 g, 15 mmol) was added toa mixture of 3-hydroxymethyl-10-methylphenothiazine (1.22 g, 5.0 mmol)and dichloromethane (15 ml), and the mixture was stirred at 0° C. for 30minutes and then at room temperature for 18 hours. The reaction mixturewas diluted with ethyl acetate, washed with a saturated sodiumbicarbonate aqueous solution and saturated sodium chloride aqueoussolution in that order, dried over anhydrous magnesium sulfate, and thenconcentrated under a reduced pressure. The resulting residue waspurified by silica gel column chromatography (eluent; ethylacetate:hexane=1:3 then 1:0) to give the title compound (1.23 g, 4.47mmol, 89%) as yellow crystals.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 3.70 (3H, s), 4.75 (2H, s), 7.25-7.30 (3H, m), 7.60-7.65 (2H, m),8.05-8.10 (2H, m).

Reference Example 21

3-Chloromethyl-10-methylphenothiazine

With ice-cooling, methanesulfonyl chloride (3.9 ml, 50 mmol) was addeddropwise to a mixture of 3-hydroxy-10-methylphenothiazine (10.9 g, 45mmol), triethylamine (8.2 ml, 59 mmol) and dichloromethane (80 ml), andthe mixture was stirred at room temperature for 1 hour. Water was addedto the reaction mixture and the reaction product was extracted withchloroform. The extract was washed with a saturated sodium bicarbonateaqueous solution and saturated sodium chloride aqueous solution in thatorder, dried over anhydrous magnesium sulfate, and concentrated under areduced pressure to give the title compound (8.09 g, 30.9 mmol, 69%) asyellow crystals.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 3.36 (3H, s), 4.47 (2H, s), 6.71 (1H, d), 6.77 (1H, d), 6.93 (1H, m),7.10-7.20 (4H, m).

The compound of Reference Example 22 was obtained in the same manner asin Reference Example 21.

Reference Example 22

3-Chloromethyl-10-methylphenothiazine-5-oxide

Material compounds: 3-hydroxymethyl-10-methylphenothiazine-5-oxide andmethanesulfonyl chloride

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 3.77 (3H, s), 4.65-4.70 (2H, m), 7.28 (1H, m), 7.35-7.40 (2H, m),7.60-7.65 (2H, m), 7.90-7.95 (2H, m).

Reference Example 23

3-Chloromethyl-10-methylphenothiazine-5,5-dioxide

Thionyl chloride (5 ml) was added to a mixture of3-hydroxymethyl-10-methylphenothiazine-5,5-dioxide (1.23 g, 4.47 mmol)and chloroform (15 ml), and the mixture was stirred for 1 hour. Thereaction mixture was concentrated under a reduced pressure, water wasadded to the residue, and the reaction product was extracted withchloroform. The extract was washed with water and saturated sodiumchloride aqueous solution in that order, dried over anhydrous magnesiumsulfate, and then concentrated under a reduced pressure to give thetitle compound (1.32 g, 100%) as colorless crystals.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 3.71 (3H, s), 4.64 (2H, s), 7.25-7.30 (3H, m), 7.60-7.65 (2H, m),8.05-8.10 (2H, m).

Reference Example 24

3-(2,2-Dibromovinyl)-10-methylphenothiazine

In an atmosphere of argon, carbon tetrabromide (8.29 g, 25 mmol) andzinc powder (1.63 g, 25 mmol) were added in that order to a mixture oftriphenylphosphine (6.56 g, 25 mmol) and dichloromethane (75 ml), andthe mixture was stirred at room temperature for 23 hours. Adichloromethane (25 ml) solution of 3-formyl-10-methylphenothiazine(3.02 g, 12.5 mmol) was added and the mixture was again stirred for 7hours. The reaction mixture was diluted with hexane and the insolublematter was removed by filtration. The reaction product was extractedfrom the insoluble matter three times with hexane (about 60° C.), andthe thus collected organic layers were combined and concentrated under areduced pressure. The resulting residue was purified by silica gelcolumn chromatography (eluent; ethylacetate:dichloromethane:hexane=10:10:80) to give the title compound(3.15 g, 7.93 mmol, 63%) as yellow crystals.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 3.36 (3H, s), 6.75 (1H, d), 6.79 (1H, d), 6.93 (1H, m), 7.10-7.15(2H, m), 7.30-7.35 (3H, m).

Reference Example 25

2-Bromomethyl-9H-xanthen-9-one

Benzoyl peroxide (4.6 g, 19 mmol) and N-bromosuccinimide (67.6 g, 380mmol) were added to a mixture of 2-methyl-9H-xanthen-9-one (79.9 g, 380mmol) and carbon tetrachloride (800 ml) with heating under reflux, andthe mixture was stirred for 4 hours. After spontaneous cooling to roomtemperature, water was added to the reaction mixture, and the reactionproduct was extracted with chloroform. The extract was washed withsaturated sodium bicarbonate aqueous solution, water and saturatedsodium chloride aqueous solution in that order, dried over anhydrousmagnesium sulfate, and then concentrated under a reduced pressure. Theresulting residue was recrystallized from ethyl acetate to give thetitle compound (78.3 g, 271 mmol, 71%) as yellow crystals.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 4.61 (2H, s), 7.39 (1H, m), 7.45-7.50 (2H, m), 7.65-7.75 (2H, m),8.30-8.35 (2H, m).

Reference Example 26

Borane- 3-(10-methylphenothiazin-3-ylmethoxy)quinuclidine! complex

In an atmosphere of argon, sodium hydride (60 wt. %, 1.16 g, 29 mmol)was added to a mixture of borane-(3-quinuclidinol) complex (3.38 g, 24mmol) and DMF (35 ml), and the mixture was stirred for 1 hour. Withice-cooling, a DMF (30 ml) solution of3-chloromethyl-10-methylphenothiazine (7.98 g, 30.5 mmol) was added tothe reaction mixture, and the mixture was stirred for 30 minutes andthen at room temperature for 30 minutes. Water was added to the reactionmixture and the reaction product was extracted with ethyl acetate. Theextract was washed with water and saturated sodium chloride aqueoussolution in that order, dried over anhydrous magnesium sulfate, and thenconcentrated under a reduced pressure. The resulting residue waspurified by silica gel column chromatography (eluent; ethylacetate:dichloromethane:hexane=10:10:80, then 15:15:70) to give thetitle compound (5.09 g, 13.9 mmol, 58%) as yellow foam.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.55-1.65 (2H, m), 1.83 (1H, m), 2.07 (1H, m), 2.02 (1H, m),2.85-3.00 (4H, m), 3.05 (1H, m), 3.18 (1H, m), 3.37 (3H, s), 3.67 (1H,m), 4.37 (1H, d), 4.41 (1H, d), 6.78 (1H, d), 6.81 (1H, d), 6.93 (1H,m), 7.05-7.20 (4H, m).

The compound of Reference Example 27 was obtained in the same manner asin Reference Example 26.

Reference Example 27

Borane- 10-methyl-3-(3-quinuclidinyloxymethyl)phenothiazine-5-oxide!complex

Material compounds: 3-chloromethyl-10-methylphenothiazine-5-oxide andborane-(3-quinuclidinol) complex

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.60-1.65 (2H, m), 1.86 (1H, m), 2.09 (1H, m), 2.27 (1H, m),2.85-3.00 (4H, m), 3.07 (1H, m), 3.23 (1H, m), 3.74 (1H, m), 3.77 (3H,s), 4.50-4.60 (2H, m), 7.25 (1H, m), 7.35-7.40 (2H, m), 7.56 (1H, m),7.63 (1H, m), 7.86 (1H, m), 7.92 (1H, m).

Reference Example 28

Borane- 3-(10-ethylphenothiazin-3-ylmethoxy)quinuclidine! complex

In an atmosphere of argon, thionyl chloride (0.65 ml, 8.86 mmol) wasadded at 0° C. to a mixture of 10-ethyl-3-hydroxymethylphenothiazine(1.14 g, 4.43 mmol), DMF (0.1 ml) and methylene chloride (12 ml), andthe mixture was stirred for 1 hour and then at room temperature for 1hour. The reaction mixture was concentrated under a reduced pressure,and chloroform and a saturated sodium bicarbonate aqueous solution (each20 ml) were added to the residue in that order. The reaction product wasextracted with ethyl acetate, and the extract was washed with saturatedsodium chloride aqueous solution. The extract was dried over anhydrousmagnesium sulfate, and then concentrated under a reduced pressure togive 3-chloromethyl-10-ethylphenothiazine (1.17 g, 4.24 mmol, 96%) asbrown oil.

In an atmosphere of argon, sodium hydride (60 wt. %, 195 mg, 4.43 mmol)was added at 0° C. to a mixture of borane-(3-quinuclidinol) complex (558mg, 4.43 mmol) and DMF (8 ml), and the mixture was stirred for 30minutes. A mixture of 3-chloromethyl-10-ethylphenothiazine (1.17 g, 4.24mmol) and DMF (4 ml) were added, and the mixture was again stirred for 1hour. The reaction mixture was concentrated under a reduced pressure,ethyl acetate and saturated sodium chloride aqueous solution (each 30ml) were added to the residue in that order, and the reaction productwas extracted with ethyl acetate. The extract was dried over anhydrousmagnesium sulfate and then concentrated under a reduced pressure. Theresulting residue was purified by silica gel column chromatography(eluent; hexane:ethyl acetate=3:1) to give the title compound (1.28 g,3.37 mmol, 79%) as yellow oil.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 0.98 (3H, brs), 1.18-2.30 (8H, m), 2.81-3.18 (6H, m), 3.60-3.74 (1H,m), 3.92 (2H, q, J=7 Hz), 4.37 (2H, s), 6.76-7.25 (7H, m).

The compounds of Reference Examples 29 to 31 were obtained in the samemanner as in Reference Example 28.

Reference Example 29

Borane- 3-(10-butylphenothiazin-3-ylmethoxy)quinuclidine! complex

Material compounds: 3-hydroxymethyl-10-butylphenothiazine,borane-(3-quinuclidinol) complex

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 0.75-1.04 (6H, m), 1.19-1.91 (8H, m), 2.15-2.30 (1H, m), 2.71-3.17(6H, m), 3.86 (2H, t, J=8 Hz), 3.91-4.16 (1H, m), 4.39 (2H, s),6.79-7.36 (7H, m).

Reference Example 30

Borane- 3- 10-(1-methylethyl)phenothiazin-3-ylmethoxy!quinuclidine!complex

Material compounds: 3-hydroxymethyl-10-(1-methylethyl)phenothiazine,borane-(3-quinuclidinol) complex

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 0.90 (3H, brs), 1.12-1.35 (4H, m), 2.15-2.30 (1H, m), 2.71-3.17 (6H,m), 3.86 (2H, t, J=8 Hz), 3.91-4.16 (1H, m), 4.39 (2H, s), 6.79-7.36(7H, m).

Reference Example 31

Borane- 3-(3-chloro-10-methylphenoxazin-7-ylmethoxy)quinuclidine!complex

Material compounds: 3-hydroxymethyl-10-methylphenoxazine,borane-(3-quinuclidinol) complex

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 0.85 (3H, brs), 1.48-1.98 (3H, m), 2.01-2.27 (2H, m), 2.79-3.20 (9H,m), 3.60-3.80 (1H, m), 4.32 (2H, s), 6.34-6.83 (6H, m).

Reference Example 32

Borane- (9H-xanthen-9-on-3-ylmethoxy)quinuclidine! complex

A mixture of 3-methyl-9H-xanthen-9-one (1.62 g, 7.71 mmol),N-bromosuccinic acid imide (1.37 g, 7.71 mmol), benzoyl peroxide (93 mg,0.39 mmol) and carbon tetrachloride (15 ml) was heated under reflux for15 hours. The insoluble matter was removed by filtration and theresulting filtrate was concentrated under a reduced pressure to give3-bromomethyl-9H-xanthen-9-one (2.19 g, 7.57 mmol, 98%) as colorlesscrystals.

In an atmosphere of argon, sodium hydride (60 wt. %, 339 mg, 7.71 mmol)was added at 0° C. to a mixture of borane- 3-hydroxyquinuclidine!complex (1.20 g, 7.71 mmol) and DMF (15 ml), and the resulting mixturewas stirred for 30 minutes. A mixture of 3-bromomethyl-9H-xanthen-9-one(2.19 g, 7.57 mmol) and DMF (8 ml) were added, and the mixture was againstirred for 1 hour. The reaction mixture was concentrated under areduced pressure, ethyl acetate and saturated sodium chloride aqueoussolution (each 50 ml) were added to the resulting residue in that order,and then the reaction product was extracted with ethyl acetate. Theextract was dried over anhydrous magnesium sulfate and then concentratedunder a reduced pressure. The resulting residue was purified by silicagel column chromatography (eluent; hexane:ethyl acetate=3:2) to give thetitle compound (260 mg, 0.74 mmol, 9.7%) as colorless crystals.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 0.92 (3H, brs), 1.18-1.35 (1H, m), 1.51-1.96 (2H, m), 1.98-2.38 (2H,m), 2.85-3.29 (6H, m), 3.73-3.90 (1H, m), 4.64 (2H, s), 7.21-7.85 (4H,m), 8.23-8.36 (2H, m).

The compound of Reference Example 33 was obtained in the same manner asin Reference Example 32.

Reference Example 33

Borane- (9H-xanthen-9-on-1-ylmethoxy)quinuclidine! complex

Material compounds: 1-methyl-9H-xanthen-9-one, borane-(3-quinuclidinol)complex

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 0.88 (3H, brs), 1.16-1.35 (2H, m), 1.60-1.90 (2H, m), 2.38-2.55 (1H,m), 2.89-3.35 (6H, m), 3.85-4.04 (1H, m), 5.24 (1H, d, J=12 Hz), 5.38(1H, d, J=12 Hz), 7.35-7.56 (3H, m), 7.60-7.83 (3H, m), 8.23 (1H, dd,J=2 Hz, 8 Hz).

Reference Example 34

Borane- (Z)-3- 2-(9H-xanthen-9-on-2-ylmethoxy)ethylidene!quinuclidine!complex

In an atmosphere of argon, sodium hydride (60 wt. %, 359 mg, 8.98 mmol)was added at 0° C. to a mixture of borane-(Z)-3-(2-hydroxyethylidene)quinuclidine! complex (1.50 g, 8.98 mmol) andDMF (17 ml), and the resulting mixture was stirred for 30 minutes.2-Bromomethyl-9H-xanthen-9-one (1.39 g, 8.98 mmol) was added, and themixture was again stirred for 2 hours. The reaction mixture wasconcentrated under a reduced pressure, ethyl acetate and saturatedsodium chloride aqueous solution (each 50 ml) were added to theresulting residue in that order, and then the reaction product wasextracted with ethyl acetate. The extract was dried over anhydrousmagnesium sulfate and then concentrated under a reduced pressure. Theresulting residue was purified by silica gel column chromatography(eluent; hexane:ethyl acetate=1:1) to give the title compound (970 mg,2.58 mmol, 29%) as colorless crystals.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 0.90 (3H, brs), 1.76-1.97 (4H, m), 2.48-2.62 (1H, m), 2.97-3.15 (4H,m), 3.65 (2H, s), 3.97 (2H, d, J=7 Hz), 4.62 (2H, s), 5.42-5.62 (1H, m),7.37-7.82 (5H, m), 8.27-8.40 (2H, m).

The compound of Reference Example 35 was obtained in the same manner asin Reference Example 34.

Reference Example 35

Borane- (Z)-3-2-(10-methylphenothiazin-3-ylmethoxy)ethylidene!quinuclidine! complex

Material compound: 3-chloromethyl-10-methylphenothiazine, borane-(Z)-3-(2-hydroxyethylidene)quinuclidine! complex

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.08 (3H, brs), 1.82-2.10 (4H, m), 2.51-2.64 (1H, m), 3.05-3.29 (4H,m), 3.47 (3H, s), 3.76 (2H, s), 4.01 (2H, d, J=6 Hz), 4.53 (2H, s),5.47-5.72 (1H, m), 6.86-7.33 (7H, m).

Reference Example 36

Borane- (Z)-3-(1-fluoro-2-hydroxyethylidene)quinuclidine! complex

With ice-cooling, sodium diisobutyl aluminum hydride (1.01M toluenesolution, 634 ml, 640 mmol) was added dropwise to a mixture of borane-ethyl (Z)-fluoro-(3-quinuclidinylidene)acetate! complex (66.1 g, 291mmol, E/Z mixture) and toluene (200 ml) spending 1.5 hours, and themixture was stirred for 0.5 hour. Methanol (60 ml), ethyl acetate (500ml) and water (500 ml) were added to the reaction mixture in that orderand the mixture was stirred at room temperature. The insoluble matterwas removed by filtration and the reaction product was extracted withethyl acetate. The extract was washed with saturated sodium chlorideaqueous solution, dried over anhydrous magnesium sulfate, and thenconcentrated under a reduced pressure. The resulting residue waspurified by silica gel column chromatography (eluent; ethylacetate:dichloromethane:hexane=20:10:70, then 30:10:60) to give thetitle compound (10.0 g, 54 mmol, 19%) and borane-(E)-3-(1-fluoro-2-hydroxyethylidene)quinuclidine! complex (25.4 g, 47%),both as colorless crystals.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.30-1.80 (3H, br), 1.80-1.95 (5H, m), 1.99 (1H, m), 3.00-3.15 (4H,m), 3.67 (2H, s), 4.13 (2H, m).

The compound of Reference Example 37 was obtained in the same manner asin Reference Example 4.

Reference Example 37

Borane- (Z)-3- 2-(carbazol-2-yloxy)-1-fluoroethylidene!quinuclidine!complex

Material compounds: borane-(Z)-3-(1-fluoro-2-hydroxyethylidene)quinuclidine! complex,2-hydroxycarbazole

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.65-1.96 (4H, m), 2.72-3.12 (5H, m), 3.75 (2H, d, J=21 Hz),6.78-6.97 (2H, m), 7.09-7.41 (3H, m), 7.70-8.03 (2H, m).

The compound of Reference Example 38 was obtained in the same manner asin Reference Example 25.

Reference Example 38

4-Bromomethyl-9H-xanthen-9-one

Material compound: 4-methyl-9H-xanthen-9-one

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 4.84 (2H, s), 7.35-7.45 (2H, m), 7.61 (1H, d, J=9 Hz), 7.76-7.80 (2H,m), 8.33-8.37 (2H, m).

Reference Example 40

2-Hydroxy-9H-xanthen-9-one

Boron tribromide (1.0M dichloromethane solution, 50 ml, 50 mmol) wasadded to a mixture of 2-methoxy-9H-xanthen-9-one (5.66 g, 25.0 mmol) anddichloromethane (50 ml), and the mixture was stirred for 3 hours. Thereaction mixture was poured into ice water and the reaction product wasextracted with chloroform. The extract was washed with water andsaturated sodium chloride aqueous solution in that order, dried overanhydrous magnesium sulfate, and then concentrated under a reducedpressure to give the title compound (5.00 g, 23.6 mmol, 94%) as yellowcrystals.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 7.30-7.40 (3H, m), 7.48 (1H, d), 7.70-7.75 (2H, m), 8.30 (1H, m),9.20 (1H, s).

Example 1

1) (E)-3- 2-(Carbazol-2-yloxy)-1-fluoroethylidene!quinuclidine

After dissolving borane-(E)-3-(2-chloro-1-fluoroethylidene)quinuclidine! complex (106.5 g, 304mmol) in acetone (2.3 l) while heating under reflux, a hydrogen chlorideethanol solution (about 5M, 300 ml) was added to the resulting solutionwhile cooling with ice-water both spending 5 minutes (inner temperature,18° to 23° C.). The reaction mixture was stirred at room temperature for1 hour, diluted with diethyl ether (2.0 l), and then the thusprecipitated crystals were collected by filtration and dried. Theresulting crystals were added to a mixture of potassium carbonate (200g), water (800 ml) and chloroform (1.2 l), the mixture was stirred at50° C. for 1 hour, and the crystals were collected by filtration (72.1g). They were combined with other portion of crystals (22.2 g) obtainedby extraction of the filtrate with chloroform, and the combinedcrystals, 94.1 g in total; were recrystallized from dioxane to give thetitle compound 84.5 g, 251 mmol, 83%).

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.60-1.70 (4H, m), 2.81 (2H, m), 2.90 (2H, m), 3.02 (1H, m), 3.52(2H, d), 4.60 (2H, d), 6.90 (1H, dd), 6.97 (1H, d), 7.21 (1H, m),7.30-7.40 (2H, m), 7.95 (1H, d), 7.98 (1H, d), 8.09 (1H, brs).

2) (E)-3- 2-(Carbazol-2-yloxy)-1-fluoroethylidene!quinuclidinehydrochloride

After dissolving (E)-3-2-(carbazol-2-yloxy)-1-fluoroethylidene!quinuclidine (95.5 g, 284 mmol)in ethanol (7.0 l) while heating under reflux, a hydrogen chlorideethanol solution (about 5M, 90 ml) was added to the resulting solutionwith ice-cooling, spending 3 minutes. After additional 0.5 hour ofice-cooling, the thus precipitated crystals were collected by filtrationand dried to give the title compound (85.2 g, 228 mmol, 80%).

Melting point: 241°-243° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.80-1.86 (2H, m), 1.95-2.02 (2H, m), 3.14-3.33 (4H, m), 4.10 (2H,s), 4.76 (2H, d, J=20 Hz), 6.82-6.84 (1H, m), 7.03-7.04 (1H, m),7.10-7.13 (1H, m), 7.28-7.32 (1H, m), 7.44-7.47 (1H, m), 7.79-8.01 (2H,m), 10.85 (1H, brs), 11.25 (1H, brs).

The following compounds of Examples 2 to 5 were obtained in the samemanner as in Example 1.

Example 2

(Z)-3- 2-(Carbazol-2-yloxy)ethylidene!quinuclidine hydrochloride

Material compound: borane- (Z)-3-2-(carbazol-2-yloxy)ethylidene!quinuclidine! complex

Melting point: 251°-253° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.80-1.88 (2H, m), 1.93-2.02 (2H, m), 2.70-2.74 (1H, m), 3.22-3.32(4H, m), 4.14 (2H, s), 4.60 (2H, d, J=7 Hz), 5.74-5.76 (1H, m),6.76-6.80 (1H, m), 6.98-7.00 (1H, m), 7.10-7.14 (1H, m), 7.28-7.32 (1H,m), 7.62 (1H, d, J=8 Hz), 7.94-8.00 (2H, m), 10.54 (1H, brs), 11.17 (1H,brs).

Example 3

(Z)-3- 2-(Carbazol-2-yloxy)-1-methylethylidene!quinuclidinehydrochloride

Material compound: borane- (Z)-3-2-(carbazol-2-yloxy)-1-methylethylidene!quinuclidine! complex

Melting point: 259°-262° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.74-1.82 (5H, m), 1.92-2.00 (2H, m), 3.03-3.04 (1H, m), 3.21-3.29(4H, m), 4.08 (2H, s), 4.51 (2H, s), 6.78-6.81 (1H, m), 6.99 (1H, s),7.09-7.12 (1H, m), 7.27-7.30 (1H, m), 7.43 (1H, d, J=8 Hz), 7.96-8.00(2H, m), 10.73 (1H, brs).

Example 4

Ethyl (z)- 2- 2-(3-quinuclidinylidene)ethoxy!carbazol-9-yl!acetatehydrochloride

Material compound: borane- ethyl (Z)- 2-2-(3-quinuclidinylidene)ethoxy!carbazol-9-yl!acetate! complex

Melting point: 138°-141° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.21 (3H, t, J=7 Hz), 1.78-1.88 (2H, m), 1.82-2.00 (2H, m), 2.68-2.70(1H, m), 3.20-3.31 (4H, m), 4.11 (2H, s), 4.16 (2H, q, J=7 Hz), 4.62(2H, d, J=7 Hz), 5.29 (2H, s), 5.72-5.76 (1H, m), 6.84-6.86 (1H, m),7.14-7.20 (2H, m), 7.33-7.36 (1H, m), 7.45 (1H, d, J=8 Hz), 8.01-8.04(2H, m), 10.61 (1H, brs).

Example 5

(Z)-3- 2- 9-(2-Aminoethyl)carbazol-2-yloxy!ethylidene!quinuclidinedihydrochloride

Material compound: borane- (Z)-3- 2-9-(2-aminoethyl)carbazol-2-yloxy!ethylidene!quinuclidine! complex

Melting point: 244°-250° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.80-1.88 (2H, m), 1.92-2.00 (2H, m), 2.68-2.71 (1H, m), 3.16-3.22(2H, m), 3.26-3.33 (4H, m), 4.12 (2H, s), 4.69-4.73 (4H, m), 5.76-5.78(1H, m), 6.85 (1H, d, J=7 Hz), 7.18-7.21 (1H, m), 7.37-7.40 (1H, m),7.48 (1H, s), 7.64 (1H, s), 8.01-8.06 (2H, m), 8.49 (3H, brs), 10.82(1H, brs).

Example 6

(Z)-3- 2-(9-Methylcarbazol-2-yloxy)ethylidene!quinuclidine hydrochloride

In an atmosphere of argon, sodium hydride (60 wt. %, 0.15 g, 3.83 mmol)was added at 0° C. to a mixture of borane- (Z)-3-2-(9-methylcarbazol-2-yloxy)ethylidene!quinuclidine! complex (1.06 g,3.19 mmol) and DMF (9 ml), and the resulting mixture was stirred for 30minutes. Methyl iodide (0.24 ml, 3.83 mmol) was added, and the mixturewas again stirred for 1 hour. The reaction mixture was concentratedunder a reduced pressure, ethyl acetate and saturated sodium chlorideaqueous solution (each 20 ml) were added to the resulting residue inthat order, and the reaction product was extracted with ethyl acetate.Then, the extract was dried over anhydrous magnesium sulfate andconcentrated under a reduced pressure to give colorless crystals (1.22g). To a mixture thereof with acetone (25 ml) was added a hydrogenchloride ethanol solution (about 5M, 5 ml) at room temperature, and theresulting mixture was stirred for 30 minutes and then diluted withdiethyl ether (25 ml). The precipitate was collected by filtration anddried under a reduced pressure to give the title compound (1.10 g, 2.98mmol, 93%) as colorless crystals.

Melting point: 241°-244° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.82-1.88 (2H, m), 1.94-2.00 (2H, m), 2.71-2.72 (1H, m), 3.21-3.27(4H, m), 3.84 (3H, s), 4.12 (2H, s), 4.66 (2H, d, J=6 Hz), 5.77-5.79(1H, m), 6.82-6.84 (1H, m), 7.15-7.17 (1H, m), 7.36-7.39 (1H, m),7.52-7.53 (1H, m), 8.01-8.04 (2H, m), 10.87 (1H, brs).

The following compounds of Examples 7 to 10 were obtained in the samemanner as in Example 6.

Example 7

(Z)-3- 2-(9-Butylcarbazol-2-yloxy)ethylidene!quinuclidine hydrochloride

Material compounds: borane- (Z)-3-2-(carbazol-2-yloxy)ethylidene!quinuclidine! complex, butyl iodide

Melting point: 202°-204° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 0.89 (3H, t, J=7 Hz), 1.27-1.35 (2H, m), 1.71-1.77 (2H, m), 1.80-1.84(2H, m), 1.94-2.00 (2H, m), 2.70-2.72 (1H, m), 3.21-3.34 (4H, m), 4.13(2H, s), 4.35 (2H, t, J=7 Hz), 5.76-5.78 (1H, m), 6.81-6.83 (1H, m),7.12-7.16 (1H, m) , 7.34-7.37 (1H, m), 7.52 (1H, d, J=9 Hz), 8.00-8.03(2H, m), 10.81 (1H, brs).

Example 8

(Z)-3- 2-(9-Benzylcarbazol-2-yloxy)ethylidene!quinuclidine hydrochloride

Material compounds: borane- (Z)-3-2-(carbazol-2-yloxy)ethylidene!quinuclidine! complex, benzyl bromide

Melting point: 220°-222° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.74-1.82 (2H, m), 1.90-1.98 (2H, m), 2.66-2.70 (1H, m), 3.16-3.24(2H, m), 3.28-3.34 (2H, m), 4.10 (2H, s), 4.60 (2H, d, J=6 Hz), 5.63(2H, s), 5.72-5.74 (1H, m), 6.85 (1H, dd, J=2 Hz, 9 Hz), 7.15-7.34 (8H,m), 7.52 (1H, d, J=9 Hz), 8.04-8.07 (2H, m), 10.48 (1H, brs).

Example 9

(Z)-3- 2- 9-2-(dimethylamino)ethyl!carbazol-2-yloxy!ethylidene!quinuclidinedihydrochloride

Material compounds: borane- (Z)-3-2-(carbazol-2-yloxy)ethylidene!quinuclidine! complex,2-dimethylaminoethyl chloride hydrochloride, sodium iodide

Melting point: 213°-216° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.80-1.90 (2H, m), 1.94-2.04 (2H, m), 2.71-2.73 (1H, m), 2.85 (6H,s), 3.26-3.33 (4H, m), 3.40 (2H, t, J=7 Hz), 4.15 (2H, s), 4.85 (2H, t,J=7 Hz), 5.78-5.81 (1H, m), 6.87 (1H, d, J=8 Hz), 7.18-7.22 (1H, m),7.38-7.42 (1H, m), 7.51 (1H, s), 7.72 (1H, d, J=8 Hz), 8.03-8.06 (2H,m), 10.76 (1H, brs), 11.67 (1H, brs).

Example 10

(Z)- 2- 2-(3-quinuclidinylidene)ethoxy!carbazol-9-yl!acetamidehydrochloride

Material compounds: borane- (Z)-3-2-(carbazol-2-yloxy)!ethylidene!quinuclidine! complex, chloroacetamide,sodium iodide

Melting point: 252°-255° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.78-1.88 (2H, m), 1.92-2.00 (2H, m), 2.68-2.72 (1H, m), 3.12-3.35(4H, m), 4.12 (2H, s), 4.64 (2H, d, J=6 Hz), 4.96 (2H, s), 5.70-5.76(1H, m), 6.84 (1H, d, J=9 Hz), 7.10 (1H, s), 7.11-7.18 (1H, m), 7.27(1H, s), 7.33-7.36 (1H, m), 7.43 (1H, d, J=8 Hz), 7.73 (1H, s), 8.02(2H, t, J=8 Hz), 10.73 (1H, brs).

Example 11

(Z)-3- 2- 9-(2-Methoxyethyl)carbazol-2-yloxy!ethylidene!quinuclidine

At 0° C., a hydrogen chloride ethanol solution (about 5M, 0.5 ml) wasadded to a mixture of borane- (Z)-3- 2-9-(2-hydroxyethyl)carbazol-2-yloxy!ethylidenequinuclidine!! complex (540mg, 1.38 mmol) and acetone (2.6 ml), and the mixture was stirred for 30minutes. Triethylamine (1 ml) was added to the reaction mixture, and themixture was concentrated under a reduced pressure. Chloroform and a 2Nsodium hydroxide aqueous solution (each 10 ml) were added to theresulting residue in that order. The reaction product was extracted withchloroform. The extract was dried over anhydrous magnesium sulfate andconcentrated under a reduced pressure. The resulting residue waspurified by silica gel column chromatography (eluent;chloroform:methanol:17% aqueous ammonia=100:3:0.3) and thenrecrystallized from diethyl ether to give the title compound (440 mg,1.17 mmol, 85%) as colorless crystals.

Melting point: 90°-91° C.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.64-1.67 (4H, m), 2.35-2.36 (1H, m), 2.62-2.68 (2H, m), 2.75-2.81(2H, m), 3.56 (2H, s), 4.01 (2H, t, J=5 Hz), 4.39 (2H, t, J=5 Hz), 4.49(2H, d, J=6 Hz), 5.47-5.49 (1H, m), 6.83-6.85 (1H, m), 6.96 (1H, s),7.18-7.21 (1H, m), 7.36-7.43 (2H, m), 7.34-7.99 (2H, m).

Example 12

The following compound of Example 12 was obtained in the same manner asin Example 11.

(Z)-3- 2- 9-(2-Hydroxyethyl)carbazol-2-yloxy!ethylidene!quinuclidine

Material compound: borane- (Z)-3- 2-9-(2-hydroxyethyl)carbazol-2-yloxy!!ethylidene!quinuclidine! complex

Melting point: 146°-148° C.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.73-1.76 (4H, m), 2.42-2.43 (1H, m), 2.85-2.97 (4H, m), 3.31 (3H,s), 3.64 (2H, s), 3.76 (2H, t, J=6 Hz), 4.42 (2H, t, J=6 Hz), 4.59 (2H,d, J=6 Hz), 5.55-5.57 (1H, m), 6.88 (1H, dd, J=9 Hz), 6.94 (1H, s),7.18-7.21 (1H, m), 7.36-7.39 (2H, m), 7.93-7.98 (2H, m).

Example 13

3-(9H-Xanthen-9-on-2-ylmethoxy)quinuclidine hydrochloride

In an atmosphere of argon, sodium hydride (60 wt. %, 69 mmol) was addedto a DMF (100 ml) solution of borane-(3-quinuclidinol) complex (8.46 g,60 mmol), and the mixture was stirred for 30 minutes and then cooledwith ice. 2-Bromomethyl-9H-xanthen-9H-one (19.1 g, 66 mmol) was added tothe reaction mixture, and the mixture was stirred for 1 hour. Then,water was added, and the reaction product was extracted with chloroform.The extract was washed with water and saturated sodium chloride aqueoussolution in that order, dried over anhydrous magnesium sulfate, and thenconcentrated under a reduced pressure. Acetone (150 ml) and a hydrogenchloride ethanol solution (ca. 5M, 60 ml) were added to the resultingresidue in that order, and the mixture was stirred for 20 minutes andthen concentrated under a reduced pressure. A potassiumcarbonate-aqueous solution (ca. 30 wt. %, 280 g) was added to theresidue. The reaction product was extracted with chloroform, dried overanhydrous magnesium sulfate, and then concentrated under a reducedpressure. The resulting yellow oil was purified by silica gel columnchromatography (eluent; 29% aqueous ammonia:methanol:chloroform=1:10:90)to give 3-(9H-xanthen-9-on-2-ylmethoxy)quinuclidine as yellow oil. Thiswas dissolved in ethyl acetate (100 ml), 4N hydrogen chloride-ethylacetate (7.5 ml) was added, and the thus precipitated crystals werecollected by filtration to give the title compound (9.05 g, 24.3 mmol,41%) as colorless crystals.

Elemental analysis (for C₂₁ H₂₁ NO₃)

    ______________________________________                                                C (%) H (%)      N (%)   Cl (%)                                       ______________________________________                                        Calcd.    67.83   5.96       3.77  9.53                                       Found     67.69   5.99       3.77  9.74                                       ______________________________________                                    

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.70-1.75 (2H, m), 1.91 (1H, m), 2.05 (1H, m), 2.40 (1H, m),3.05-3.25 (5H, m), 3.55 (1H, m), 4.00 (1H, m), 4.66 (1H, d), 4.70 (1H,d), 7.49 (1H, dd), 7.65-7.70 (2H, m), 7.85-7.95 (2H, m), 8.15-8.25 (2H,m), 10.80 (1H, brs).

The following compounds of Examples 14 to 16 were obtained in the samemanner as Example 13.

Example 14

(R)-3-(9H-Xanthen-9-on-2-ylmethoxy)quinuclidine hydrochloride

Material compounds: 2-bromomethyl-9H-xanthen-9-one, borane-(R)-3-quinuclidinol! complex

Mass spectrometry data (m/z): 335 (M⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.65-1.75 (2H, m), 1.90 (1H, m), 2.04 (1H, m), 2.40 (1H, m),3.05-3.20 (5H, m), 3.55 (1H, m), 3.99 (1H, m), 4.66 (1H, d), 4.70 (1H,d), 7.50 (1H, dd), 7.65-7.70 (2H, m), 7.85-7.95 (2H, m), 8.15-8.25 (2H,m), 10.45 (1H, brs).

Example 15

(S)-3-(9H-Xanthen-9-on-2-ylmethoxy)quinuclidine hydrochloride

Material compounds: 2-bromomethyl-9H-xanthen-9-one, borane-(S)-3-quinuclidinol! complex

Mass spectrometry data (m/z): 335 (M⁺)

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.70-1.75 (2H, m), 1.91 (1H, m), 2.05 (1H, m), 3.05-3.20 (5H, m),3.55 (1H, m), 3.99 (1H, m), 4.66 (1H, d), 4.70 (1H, d), 7.50 (1H, dd),7.65-7.70 (2H, m), 7.85-7.95 (2H, m), 8.15-8.25 (2H, m), 10.66 (1H,brs).

Example 16

10-Methyl-3-(3-quinuclidinyloxymethyl)phenothiazine-5,5-dioxidehydrochloride

Material compounds: 3-chloromethyl-10-methylphenothiazine-5,5-dioxide,borane-(3-quinuclidinol) complex

Melting point: 274°-276° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.65-1.70 (2H, m), 1.90 (1H, m), 2.01 (1H, m), 2.37 (1H, m),3.05-3.20 (5H, m), 3.51 (1H, m), 3.74 (3H, s), 3.95 (1H, m), 4.61 (1H,d), 4.65 (1H, d), 7.37 (1H, dd), 7.60-7.65 (2H, m), 7.75-7.80 (2H, m),7.95-8.00 (2H, m), 10.34 (1H, brs).

Example 17

3-(10-Methylphenothiazin-3-ylmethoxy)quinuclidine hydrochloride

With ice-cooling, a hydrogen chloride ethanol solution (ca. 5M, 10 ml)was added to an acetone (20 ml) solution of borane-3-(10-methylphenothiazin-3-ylmethoxy)quinuclidine! complex (5.09 g, 13.9mmol), and the mixture was stirred for 5 minutes and then diluted withdiethyl ether (40 ml). The resulting precipitate was collected byfiltration and dried under a reduced pressure to give the title compound(4.48 g, 11.5 mmol, 83%) as light green crystals.

Melting point: 220°-222° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.65-1.70 (2H, m), 1.87 (1H, m), 1.98 (1H, m), 2.31 (1H, m),2.95-3.15 (5H, m), 3.31 (3H, s), 3.47 (1H, m), 3.86 (1H, m), 4.39 (1H,d), 4.44 (1H, d), 6.90-7.00 (3H, m), 7.15-7.25 (4H, m).

The following compounds of Examples 18 to 22 were obtained in the samemanner as Example 17.

Example 18

(R)-3-(10-Methylphenothiazin-3-ylmethoxy)quinuclidine hydrochloride

Material compound: borane-(R)-3-(10-methylphenothiazin-3-ylmethoxy)quinuclidine! complex

Melting point: 220°-221° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.65-1.70 (2H, m), 1.87 (1H, m), 1.98 (1H, m), 2.31 (1H, m),3.00-3.20 (5H, m), 3.31 (3H, s), 3.47 (1H, m), 3.87 (1H, m), 4.39 (1H,d), 4.44 (1H, d), 6.90-7.00 (3H, m), 7.15-7.25 (4H, m).

Example 19

(S)-3-(10-Methylphenothiazin-3-ylmethoxy)quinuclidine hydrochloride

Material compound: borane-(S)-3-(10-methylphenothiazin-3-ylmethoxy)quinuclidine! complex

Melting point: 214°-217° C.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.60-1.70 (2H, m), 1.88 (1H, m), 1.98 (1H, m), 2.30 (1H, m),3.00-3.20 (5H, m), 3.31 (3H, s), 3.46 (1H, m), 3.87 (1H, m), 4.39 (1H,d), 4.44 (1H, d), 6.90-7.00 (3H, m), 7.15-7.25 (4H, m).

Example 20

3-(9H-Xanthen-9-on-3-ylmethoxy)quinuclidine hydrochloride

Material compound: borane- 3-(9H-xanthen-9-on-3-ylmethoxy)quinuclidine!complex

Melting point: 246°-248° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.66-1.78 (2H, m), 1.84-1.94 (1H, m), 2.02-2.08 (1H, m), 2.40-2.44(1H, m), 3.06-3.24 (5H, m), 3.52-3.60 (1H, m), 3.98-4.04 (1H, m), 4.72(1H, d, J=14 Hz), 4.77 (1H, d, J=14 Hz), 7.45-7.52 (2H, m), 7.68-7.72(2H, m), 7.91-7.92 (1H, m), 8.19-8.22 (2H, m), 10.08 (1H, brs).

Example 21

3-(9H-Xanthen-9-on-1-ylmethoxy)quinuclidine hydrochloride

Material compound: borane- 3-(9H-xanthen-9-on-1-ylmethoxy)quinuclidine!complex

Melting point: 245°-247° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.70-1.81 (2H, m), 1.91-1.98 (1H, m), 2.04-2.13 (1H, m), 2.45-2.47(1H, m), 3.13-3.28 (5H, m), 3.59-3.65 (1H, m), 4.06-4.13 (1H, m), 5.24(2H, s), 7.46-7.50 (1H, m), 7.61-7.70 (3H, m), 7.85-7.90 (2H, m).

Example 22

(Z)-3- 2-(9H-Xanthen-9-on-2-ylmethoxy)ethylidene!quinuclidinehydrochloride

Material compound: borane- (Z)-3-2-(9H-xanthen-9-on-2-ylmethoxy)ethylidene!quinuclidine! complex

Melting point: 199°-202° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.76-1.86 (2H, m), 1.92-1.98 (2H, m), 2.64 (1H, s), 3.20-3.29 (4H,m), 3.98 (2H, s), 4.02 (2H, d, J=6 Hz), 4.63 (2H, s), 5.59-5.62 (1H, m),7.48-7.52 (1H, m), 7.68-7.70 (2H, m), 7.84-7.91 (2H, in), 8.16 (1H, s),8.21 (1H, d, J=8 Hz), 10.67 (1H, brs).

Example 23

3-(10-Ethylphenothiazin-3-ylmethoxy)quinuclidine

At 0° C., a hydrogen chloride ethanol solution (ca. 5M, 1 ml) was addedto a mixture of borane-3-(10-ethylphenothiazin-3-ylmethoxy)quinuclidine! complex (1.28 g, 3.37mmol) and acetone (5 ml), and the mixture was stirred for 30 minutes.Triethylamine (2 ml) was added to the reaction mixture, and the mixturewas concentrated under a reduced pressure. Chloroform and a 2N sodiumhydroxide aqueous solution (each 30 ml) were added to the resultingresidue in that order, and then the reaction product was extracted withchloroform. The extract was dried over anhydrous magnesium sulfate andthen concentrated under a reduced pressure. The resulting residue waspurified by silica gel column chromatography (eluent; 29% aqueousammonia:methanol:chloroform=0.3:3:97) to give the title compound (900mg, 2.46 mmol, 73%) as yellow oil.

Mass spectrometry data (m/z): 366 (M⁺) (GC)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.36-1.44 (5H, m), 1.66-1.72 (1H, m), 1.89-2.06 (2H, m), 2.66-2.82(4H, m), 2.91-2.96 (1H, m), 3.06-3.11 (1H, m), 3.53-3.55 (1H, m), 3.92(2H, q, J=7 Hz), 4.32 (1H, d, J=12 Hz), 4.42 (1H, d, J=12 Hz), 6.82-6.91(3H, m), 7.10-7.15 (4H, m).

The following compounds of Examples 24 to 28 were obtained in the samemanner as Example 23.

Example 24

3-(10-Butylphenothiazin-3-ylmethoxy)quinuclidine

Material compound: borane-3-(10-butylphenothiazin-3-ylmethoxy)quinuclidine! complex

Mass spectrometry data (m/z): 394 (M⁺) (GC)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 0.93 (3H, t, J=7 Hz), 1.37-1.49 (4H, m), 1.67-1.81 (3H, m), 1.90-1.98(1H, m), 2.06-2.07 (1H, m), 2.70-2.83 (4H, m), 2.92-2.95 (1H, m),3.08-3.12 (1H, m), 3.54-3.56 (1H, m), 3.84 (2H, t, J=7 Hz), 4.33 (1H, d,J=12 Hz), 4.42 (1H, d, J=12 Hz), 6.81-6.91 (3H, m), 7.10-7.15 (4H, m).

Example 25

3- 10-(1-Methylethyl)phenothiazin-3-ylmethoxy!quinuclidine

Material compound: borane- 3-10-(1-methylethyl)phenothiazin-3-ylmethoxy!quinuclidine! complex

Mass spectrometry data (m/z): 380 (M⁺) (GC)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.34-1.48 (2H, m), 1.62 (6H, d, J=7 Hz), 1.66-1.76 (1H, m), 2.06-2.10(1H, m), 2.70-2.86 (4H, m), 2.94-3.00 (1H, m), 3.10-3.16 (1H, m),3.35-3.57 (1H, m), 4.24-4.30 (1H, m), 4.33 (1H, d, J=12 Hz), 4.43 (1H,d, J=12 Hz), 6.89-6.92 (1H, m), 7.00-7.04 (2H, m), 7.08-7.14 (4H, m)

Example 26

10-Methyl-3-(3-quinuclidinyloxymethyl)phenothiazine-5-oxide

Material compound: borane-10-methyl-3-(3-quinuclidinyloxymethyl)phenothiazine-5-oxide! complex

Melting point: 164°-166° C.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.35-1.45 (2H, m), 1.70 (1H, m), 1.91 (1H, m), 2.09 (1H, m), 2.69(1H, m), 2.70-2.80 (2H, m), 2.93 (1H, m), 3.11 (1H, m), 3.77 (3H, s),4.51 (1H, m), 4.61 (1H, m), 7.25 (1H, m), 7.35-7.40 (2H, m), 7.60-7.65(2H, m), 7.90-7.95 (2H, m).

Example 27

3-(3-Chloro-10-methylphenoxazin-7-ylmethoxy)quinuclidine

Material compound: borane-3-(3-chloro-10-methylphenoxazin-7-ylmethoxy)quinuclidine! complex

Melting point: 89°-90° C.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.44-1.50 (2H, m), 1.70-1.75 (1H, m), 1.92-1.98 (1H, m), 2.06-2.10(1H, m), 2.72-2.86 (4H, m), 2.94-3.06 (4H, m), 3.10-3.15 (1H, m),3.56-3.58 (1H, m) , 4.28 (1H, d, J=12 Hz), 4.37 (1H, d, J=12 Hz), 6.40(1H, d, J=8 Hz), 6.48 (1H, d, J=8 Hz), 6.69 (2H, s), 6.79-6.82 (2H, m).

Example 28

(Z)-3- 2-(10-Methylphenothiazin-3-ylmethoxy)ethylidene!quinuclidine

Material compound: borane- (Z)-3-2-(10-methylphenothiazin-3-ylmethoxy)ethylidene!quinuclidine! complex

Mass spectrometry data (m/z): 379 (M⁺) (FAB)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.70-1.74 (4H, m), 2.35-2.36 (1H, m), 2.80-2.94 (4H, m), 3.37 (3H,s), 3.47 (2H, s), 3.90 (2H, d, J=6 Hz), 4.40 (2H, s), 5.34-5.37 (1H, m),6.77-6.81 (2H, m), 6.90-6.93 (1H, m), 7.13-7.17 (4H, m).

Example 29

3- (10-Methylphenothiazin-3-ylmethyl)amino!quinuclidine difumarate

At 0° C., sodium triacetoxy borohydride (1.24 g, 5.85 mmol) was added toa mixture of 3-aminoquinuclidine (405 mg, 3.21 mmol),3-formyl-10-methylphenothiazine (704 mg, 2.92 mmol), acetic acid (1.8ml) and methylene chloride (29 ml), and the mixture was stirred for 1hour. A saturated sodium bicarbonate aqueous solution (30 ml) was addedto the reaction mixture and the reaction product was extracted withchloroform. The extract was washed with saturated sodium chlorideaqueous solution, dried over anhydrous magnesium sulfate, and thenconcentrated under a reduced pressure to give a colorless foamy material(1.23 g). To a mixture thereof with ethanol (25 ml) was added fumaricacid (817 mg, 5.85 mmol), and the resulting precipitate was collected byfiltration to give the title compound (1.41 g, 2.42 mmol, 83%) as yellowcrystals.

Melting point: 182°-184° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.54-1.66 (2H, m), 1.78-1.86 (1H, m), 2.06-2.12 (2H, m), 2.75 (1H, d,J=13 Hz), 2.94-3.18 (6H, m), 3.30 (3H, s), 3.33-3.37 (1H, m), 3.57-3.66(2H, m), 6.54 (4H, s), 6.89-6.96 (3H, m), 7.15-7.23 (4H, m)

Example 30

3-Hydroxy-3- 2-(10-methylphenothiazin-3-yl)ethyl!quinuclidine

In an atmosphere of argon, a hexane solution of n-butyl lithium (1.65M,10.1 ml, 16.7 mmol) was added at -78° C. to a THF (25 ml) solution of3-(2,2-dibromovinyl)-10-methylphenothiazine (3.13 g, 7.94 mmol), and themixture was stirred for 1 hour and then at room temperature for 1 hour.The reaction mixture was again cooled at -78° C., and a THF (8 ml)solution of 3-quinuclidinone (1.09 g, 8.70 mmol) was added dropwise. Themixture was stirred at -78° C. for 1 hour and then with ice-cooling for30 minutes. Water (5 ml) was added to the reaction mixture and themixture was concentrated under a reduced pressure. A potassium carbonateaqueous solution was added and the reaction product was extracted withchloroform which was heated at about 50° C. The extract was dried overanhydrous magnesium sulfate and then concentrated under a reducedpressure. The resulting residue was recrystallized fromethanol-chloroform to give the title compound (1.75 g, 4.83 mmol, 61%)as yellow crystals.

Melting point: 210°-213° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.28 (1H, m), 1.55 (1H, m), 1.80-1.95 (3H, m), 2.65-2.70 (4H, m),2.81 (1H, d), 3.04 (1H, d), 3.31 (1H, s), 5.53 (1H, s), 6.91 (l1H, d),6.95-6.70 (2H, m), 7.15-7.25 (4H, m).

Example 31

3-Hydroxy-3-quinuclidinylmethyl 10-methyl-2-phenothiazinyl ketone

In an atmosphere of argon, a hexane solution of n-butyl lithium (1.71M,4.94 ml, 8.45 mmol) was added at -78° C. to a THF (8 ml) solution ofdiisopropylamine (1.23 ml, 8.8 mmol), and the mixture was stirred for 40minutes. To the solution of the resulting lithium diisopropylamide wasadded a THF (8 ml) solution of 2-acetyl-10-methylphenothiazine (1.96 g,7.68 mmol), and the mixture was stirred for 1 hour. A THF (8 ml)solution of 3-quinuclidinone (951 mg, 7.60 mmol) was added, the mixturewas stirred at -78° C. for 30 minutes and then with ice-cooling for 15minutes. Water was added to the reaction mixture and the reactionproduct was extracted with chloroform. The extract was washed withsaturated sodium chloride aqueous solution, dried over anhydrousmagnesium sulfate, and then concentrated under a reduced pressure. Theresulting residue was purified by silica gel column chromatography(eluent; 29% aqueous ammonia:methanol:chloroform=1:10:90) to give thetitle compound (1.55 g, 4.07 mmol, 53%) as yellow foam.

Mass spectrometry data (m/z): 380 (M⁺)

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.34 (1H, m), 1.55-1.60 (2H, m), 1.95 (1H, m), 2.17 (1H, m),2.70-2.85 (4H, m), 2.95-3.05 (2H, m), 3.19 (1H, d), 3.36 (1H, d), 3.42(3H, s), 4.13 (1H, s), 6.82 (1H, d), 6.95 (1H, m), 7.10 (1H, m),7.15-7.25 (2H, m), 7.34 (1H, s), 7.48 (1H, s).

Example 32

3-Hydroxy-3-quinuclidinylmethyl 2-phenothiazinyl ketone

In an atmosphere of argon, a hexane solution of n-butyl lithium (1.71M,6.1 ml, 10.5 mmol) was added at -78° C. to a THF (10 ml) solution ofdiisopropylamine (1.54 ml, 11 mmol), and the mixture was stirred for 40minutes. To the resulting solution of lithium diisopropylamide was addeda THF (8 ml) solution of 2-acetylphenothiazine (1.21 g, 5.0 mmol). Themixture was stirred for 30 minutes, a THF (3 ml) solution of3-quinuclidinone (626 mg, 5.0 mmol) was added, and the mixture wasstirred for 30 minutes. Water was added to the reaction mixture and thereaction product was extracted with chloroform. The extract was washedwith saturated sodium chloride aqueous solution, dried over anhydrousmagnesium sulfate, and then concentrated under a reduced pressure. Theresulting residue was purified by silica gel column chromatography(eluent; 29% aqueous ammonia:methanol:chloroform=0.8:8:92 then 2:20:80),to give the title compound (127 mg, 0.35 mmol, 7%) as yellow foam.

Melting point: 169°-171° C.

Nuclear magnetic resonance spectrum (CDCl₃, TMS internal standard)

δ: 1.39 (1H, m), 1.60-1.65 (2H, m), 1.98 (1H, m), 2.22 (1H, m),2.80-3.30 (8H, m), 4.18 (1H, brs), 6.13 (1H, brs), 6.56 (1H, d), 6.83(1H, dd), 6.92 (1H, d), 6.95-7.00 (2H, m), 7.10 (1H, s), 7.32 (1H, d).

The following compound of Example 33 was obtained in the same manner asExample 1.

Example 33

(Z)-3- 2-(Carbazol-2-yloxy)-1-fluoroethylidene!quinuclidinehydrochloride

Material compound: borane-(Z)-3-(1-fluoro-2-hydroxyethylidene)quinuclidine! complex

Melting point: 246°-249° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.76-1.82 (2H, m), 1.96-2.02 (2H, m), 3.10-3.11 (1H, m), 3.22-3.33(4H, m), 4.07 (2H, s), 4.89 (2H, d, J=22 Hz), 6.82 (1H, dd, J=3, 9 Hz),7.04 (1H, d, J=3 Hz), 7.10-7.13 (1H, m), 7.28-7.31 (1H, m), 7.43 (1H, d,J=8 Hz), 7.98-8.01 (2H, m), 10.76 (1H, s), 11.22 (1H, s).

The following compounds of Examples 34 and 35 were obtained in the samemanner as in Example 13.

Example 34

3-(9H-Xanthen-9-on)-4-ylmethoxy)quinuclidine hydrochloride

Material compounds: 4-bromomethyl-9H-xanthen-9-one,borane-(3-quinuclidinol) complex

Melting point: 226°-229° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.71-1.79 (2H, m), 1.92-1.98 (1H, m), 2.08-2.12 (1H, m), 3.08-3.21(6H, m), 3.56-3.62 (1H, m), 4.88 (1H, d, J=12 Hz), 7.72 (1H, d, J=9 Hz),7.90-7.97 (2H, m), 8.17-8.23 (2H, m), 10.47 (1H, s).

Example 35

(Z)-3- 2-(9H-Xanthen-9-on-2-yloxy)ethylidene!quinuclidine hydrochloride

Material compounds: 2-hydroxy-9H-xanthen-9-one, borane-(Z)-3-(2-hydroxyethylidene)quinuclidine! complex

Melting point: 257°-260° C.

Nuclear magnetic resonance spectrum (DMSO-d₆, TMS internal standard)

δ: 1.83 (2H, m), 1.99 (2H, m), 2.72 (1H, m), 3.20-3.35 (4H, m), 4.15(2H, s), 4.67 (2H, d), 5.74 (1H, m), 7.45-7.55 (2H, m), 7.61 (1H, d),7.65-7.70 (2H, m), 7.89 (1H, m), 8.21 (1H, dd), 10.77 (1H, brs).

Chemical structures of the compounds obtained in Examples 1 to 35 areshown in Table 3.

                                      TABLE 3                                     __________________________________________________________________________    Example                                                                              Chemical Structural Formula                                            __________________________________________________________________________            ##STR14##                                                             2                                                                                     ##STR15##                                                             3                                                                                     ##STR16##                                                             4                                                                                     ##STR17##                                                             5                                                                                     ##STR18##                                                             6                                                                                     ##STR19##                                                             7                                                                                     ##STR20##                                                             8                                                                                     ##STR21##                                                             9                                                                                     ##STR22##                                                             10                                                                                    ##STR23##                                                             11                                                                                    ##STR24##                                                             12                                                                                    ##STR25##                                                             13                                                                                    ##STR26##                                                             14                                                                                    ##STR27##                                                             15                                                                                    ##STR28##                                                             16                                                                                    ##STR29##                                                             17                                                                                    ##STR30##                                                             18                                                                                    ##STR31##                                                             19                                                                                    ##STR32##                                                             20                                                                                    ##STR33##                                                             21                                                                                    ##STR34##                                                             22                                                                                    ##STR35##                                                             23                                                                                    ##STR36##                                                             24                                                                                    ##STR37##                                                             25                                                                                    ##STR38##                                                             26                                                                                    ##STR39##                                                             27                                                                                    ##STR40##                                                             28                                                                                    ##STR41##                                                             29                                                                                    ##STR42##                                                             30                                                                                    ##STR43##                                                             31                                                                                    ##STR44##                                                             32                                                                                    ##STR45##                                                             33                                                                                    ##STR46##                                                             34                                                                                    ##STR47##                                                             35                                                                                    ##STR48##                                                             __________________________________________________________________________

We claim:
 1. A quinuclidine derivative having a tricyclic heterocondensed ring, represented by the following formula (I), a saltthereof, a hydrate thereof or a solvate thereof; ##STR49## wherein R₁ :a hydrogen atom, a halogen atom or a lower alkyl group,R₂ : a hydrogenatom, a hydroxyl group or a lower alkoxy group, . . : a single bond or adouble bond,with the proviso that R₂ does not exist when . . . is adouble bond, X and Y: the same or different from each other and eachrepresents a bond, an oxygen atom (--O--), a carbonyl group (--CO--), agroup represented by the formula --S(O)_(p) -- or a group represented bythe formula --NR₃ --,p: 0, 1 or 2, R₃ : a hydrogen atom or a lower alkylgroup which may have a substituent, A: a saturated or unsaturated loweralkylene group, a group represented by the formula --(CH₂)_(m)Z(CH₂)_(n) -- or a group represented by the formula --(CH₂)_(m)Z(CH₂)_(n) CR₄ =,Z: an oxygen atom (--O--), a group represented by theformula --S(O)_(q) --, a carbonyl group (--CO--) or a group representedby the formula --NR₅ --, R₄ : a hydrogen atom, a halogen atom or a loweralkyl group, R₅ : a hydrogen atom or a lower alkyl group, m and n: thesame or different from each other and each is 0 or an integer of 1 to 5,m+n: an integer of 1 to 5, and q: 0, 1 or 2, with the proviso that A isa group represented by the formula --(CH₂)_(m) Z(C₂)_(n) CR₄ = wheneither one of X and Y is a bond.
 2. The compound according to claim 1,wherein A is an unsaturated lower alkylene group, a group represented bythe formula --(CH₂)_(m) Z(CH₂)_(n) -- or a group represented by theformula --(CH₂)_(m) Z(CH₂)_(n) CR₄ = and Z is an oxygen atom (--O--), acarbonyl group (--CO--) or a group represented by the formula --NR₅ --.3. The compound according to claim 2, wherein the tricyclic grouprepresented by ##STR50## in the formula (I) is ##STR51##
 4. The compoundaccording to claim 3, wherein R₃ is a hydrogen atom or a lower alkylgroup which may have a hydroxyl group, a lower alkoxy group, an aminogroup, a mono- or di-lower alkylamino group, a carboxyl group, a loweralkoxycarbonyl group, a carbamoyl group, a mono- or di-loweralkylcarbamoyl group or an aryl group as its substituent.
 5. Thecompound according to claim 4, wherein A is a group represented by theformula --(CH₂)_(m) Z(CH₂)_(n) CR₄ =.
 6. The compound according to claim4, wherein A is a group represented by the formula --(C₂)_(m) O(C₂)_(n)CR₄ =.
 7. The compound according to claim 1 which is (Z)-3-2-(Carbazol-2-yloxy)ethylidene!quinuclidine, a salt thereof, a hydratethereof or a solvate thereof.
 8. (Z)-3-2-(Carbazol-2-yloxy)-1-methylethylidene!quinuclidine, a salt thereof, ahydrate thereof or a solvate thereof.
 9. (E)-3-2-(Carbazol-2-yloxy)-1-fluoroethylidene!quinuclidine, a salt thereof, ahydrate thereof or a solvate thereof.
 10. A pharmaceutical compositionwhich comprises a pharmaceutically acceptable carrier and the compoundof any one of claims 1 to 9 or a pharmaceutically acceptable saltthereof as its active ingredient.
 11. A method for selectivelyinhibiting squalene synthase activity in a patient which comprisesadministering to the patient a therapeutically effective amount of thepharmaceutical composition of claim
 10. 12. The method of claim 11wherein the compound is (z)-3-2-(Carbazol-2-yloxy)ethylidene!quinuclidine, a salt thereof, a hydratethereof or a solvate thereof.
 13. The method of claim 11 wherein thecompound is (z)-3- 2-(Carbazol-2-yloxy)-1-methylethylidene!quinuclidine,a salt thereof, a hydrate thereof or a solvate thereof.
 14. The methodof claim 11 wherein the compound is (E)-3-2-(Carbazol-2-yloxy)-1-fluoroethylidene!quinuclidine, a salt thereof, ahydrate thereof or a solvate thereof.
 15. The method of claim 11 whereinthe pharmaceutical composition is effective as a cholesterol loweringagent.
 16. The method of claim 11 wherein the pharmaceutical compositionis effective in the prevention or treatment of hyperlipemia.
 17. Themethod of claim 11 wherein the pharmaceutical composition is effectivein the prevention or treatment of arteriosclerosis, aneurysm, ischemicheart disease or cerebral arteriosclerotic disease.
 18. The method ofclaim 17 wherein the ischemic heart disease is myocardial infarction orangina pectoris.
 19. The method of claim 17 wherein the cerebralarteriosclerotic disease is cerebral infarction.